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U S M L E®

STEP

2 CK

Lecture Notes 2018

Internal Medicine


USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.

USMLE® is a joint program of the Federation of State Medical Boards (FSMB) and the

National Board of Medical Examiners (NBME), neither of which sponsors or endorses this product.

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U SM L E®

STEP 2

CK

Lecture Notes 2018

Internal Medicine



USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.



USMLE® is a joint program of the Federation of State Medical Boards (FSMB) and the National Board of Medical Examiners (NBME), neither of which sponsors or endorses this product.


This publication is designed to provide accurate information in regard to the subject matter covered as of its publication date, with the understanding that knowledge and best practice constantly evolve. The publisher is not engaged in rendering medical, legal, accounting, or other professional service.

If medical or legal advice or other expert assistance is required, the services of a competent profes- sional should be sought. This publication is not intended for use in clinical practice or the delivery of medical care. To the fullest extent of the law, neither the Publisher nor the Editors assume any liability for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this book.


© 2017 by Kaplan, Inc.


Published by Kaplan Medical, a division of Kaplan, Inc. 750 Third Avenue

New York, NY 10017


All rights reserved. The text of this publication, or any part thereof, may not be reproduced in any manner whatsoever without written permission from the publisher.


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and the National Board of Medical Examiners.


Editors

Joseph J. Lieber, MD Associate Director of Medicine Elmhurst Hospital Center


Associate Professor of Medicine

Associate Program Director in Medicine for Elmhurst Site Icahn School of Medicine at Mt. Sinai

New York, NY


Frank P. Noto, MD

Assistant Professor of Internal Medicine

Site Director, Internal Medicine Clerkship and Sub-Internship Icahn School of Medicine at Mt. Sinai

New York, NY


Hospitalist Elmhurst Hospital Center

New York, NY


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The editors would like to acknowledge

Manuel A. Castro, MD, AAHIVS, Amirtharaj Dhanaraja, MD, and Aditya Patel, MD, and Irfan Sheikh, MD for their contributions.


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We want to hear what you think. What do you like or not like about the Notes?

Please email us at medfeedback@kaplan.com.


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Table of Contents

Chapter Title


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Chapter 1: Preventive Medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1


Chapter 2: Endocrinology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11


Chapter 3: Rheumatology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61


Chapter 4: Gastroenterology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85


Chapter 5: Cardiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125


Chapter 6: Hematology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193


Chapter 7: Infectious Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225


Chapter 8: Nephrology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281


Chapter 9: Pulmonology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 321


Chapter 10: Emergency Medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 361


Chapter 11: Neurology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 405


Chapter 12: Dermatology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 433


Chapter 13: Radiology/Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 455


Chapter 14: Ophthalmology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 465


Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 473


Additional resources available at www.kaptest.com/usmlebookresources


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PreventCivheapMtedr iTciitnle #1


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Learning Objectives


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CANCER SCREENING

A 39-year-old woman comes to the clinic very concerned about her risk of developing cancer. Her father was diagnosed with colon cancer at age 43, and her mother was diagnosed with breast cancer at age 52. She is sexually active with multiple partners and has not seen a physician since a car accident 15 years ago. She denies any symptoms at this time, and her physical examination is normal. She asks what is recommended for a woman her age.


Screening tests are done on seemingly healthy people to identify those at increased risk of dis- ease. Even if a diagnostic test is available, however, that does not necessarily mean it should be used to screen for a particular disease.

Finally, there may be a stigma associated with incorrectly labeling a patient as “sick.”

For all diseases for which screening is recommended, effective intervention must exist, and the course of events after a positive test result must be acceptable to the patient. Most important, the screening test must be valid, i.e., it must have been shown in trials to decrease overall mortality in the screened population. For a screening test to be recommended for regular use, it has to be extensively studied to ensure that all of the requirements are met.


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USMLE Step 2 l Internal Medicine



Note

Tamoxifen prevents cancer by 50% in those with >1 family member with breast cancer.


Note

Prostate Screening

USPSTF concludes that the current evidence is insufficient to assess the balance of benefits/risks of prostate cancer screening in men age

<75. It recommends against screening in men age >75.

For USMLE, do not screen for prostate cancer.

The 4 malignancies for which regular screening is recommended are cancers of the colon, breast, cervix, and lung.


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Colon Cancer

In the patient with no significant family history of colon cancer, screening should begin at age

  1. The preferred screening modality for colon cancer is colonoscopy every 10 years. Other choices include annual fecal occult blood testing and sigmoidoscopy with barium enema every 5 years.

    In the patient with a single first-degree relative diagnosed with colorectal cancer before age 60 or multiple first-degree relatives with colon cancer at any age, colonoscopy should begin at age 40 or 10 years before the age at which the youngest affected relative was diagnosed, whichever age occurs earlier. In these high-risk patients, colonoscopy should be repeated every 5 years. The U.S. Preventive Services Task Force (USPSTF) does not recommend routine screening in patients age >75.


    Breast Cancer

    The tests used to screen for breast cancer are mammography and manual breast exam. Mammography with or without clinical breast exam is recommended every 1–2 years from age 50–74. The American Cancer Society no longer recommends monthly self-breast examination alone as a screening tool. Patients with very strong family histories of breast cancer (defined as multiple first-degree relatives) should consider prophylactic tamoxifen, discussing risks and benefits with a physician. Tamoxifen prevents breast cancer in high-risk individuals.


    Cervical Cancer

    The screening test of choice for the early detection of cervical cancer is the Papanicolaou smear (the “Pap” test). In average risk women, Pap smear screening should be started at age 21, regardless of onset of sexual activity. It should be performed every 3 years until age 65.

    As an alternative, women age 30–65 who wish to lengthen the screening interval to every 5 years can do co-testing with Pap and HPV testing. In higher risk women, e.g., HIV, more frequent screening or screening after age 65 may be required.


    Lung Cancer

    Current recommendations for lung cancer screening are as follows:

Diagnosis of hypothyroidism is made by symptoms and physical findings. Lab tests confirm diagnosis.


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USMLE Step 2 l Internal Medicine



Clinical Pearl



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Chapter 2 Endocrinology


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400 mg Ca2+/d

Absorption: 30–35%


PTH +


4

Calcitonin

+ –

Vit D

+ Abs Ca/PO

+

free

Ca Ca2+ Ca2+ + prot Plasma


PTH

Calcitonin

1,25 (OH)2 Vit D


Vit D


4



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4

Dietary endogenous Vit D3


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  1. OH-Vit D


    Figure 2-10. Calcium Regulation


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    USMLE Step 2 l Internal Medicine


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    Treatment. For severe, life-threatening hypercalcemia, give vigorous fluid replacement with normal or half-normal saline, followed by a loop diuretic such as furosemide to promote cal- cium loss.

Clinical Findings. 50% of patients with hyperparathyroidism are asymptomatic. Osteitis fibrosa cystica with hyperparathyroidism occurs because of increased rate of osteoclastic bone resorp- tion and results in bone pain, fractures, swelling, deformity, areas of demineralization, bone cysts, and brown tumors (punched-out lesions producing a salt-and-pepper-like appearance). Urinary tract manifestations of hypercalcemia include polyuria, polydipsia, stones, and nephrocalcinosis with renal failure (the polyuria and polydipsia are from NDI). Neurologic manifestations include CNS problems, mild personality disturbance, severe psychiatric disorders, mental obtundation or coma, neuromuscular weakness, easy fatigability, and atrophy of muscles. GI manifestations include anorexia, weight loss, constipation, nausea, vomiting, thirst, abdominal pain with pancreatitis, and peptic ulcer disease. Cardiovascular findings include hypertension and arrhyth- mias (short QT).

Diagnosis. Lab findings will include serum calcium >10.5 mg/dL, with elevated PTH. Urine calcium elevation is common, but because of the calcium-reabsorbing action of PTH, 35% of patients may have normal levels. Serum phosphate is usually low (<2.5 mg/dL). The differential diagnosis includes all other causes of hypercalcemia, especially hypercalcemia of malignancy. In every other cause of hypercalcemia, the PTH level will be low. In primary hyperparathy- roidism, PTH is always elevated.

Imaging studies such as CT, MRI, sonography, and nuclear scan are not used to diagnose hyperparathyroidism. A nuclear parathyroid scan (sestamibi) can be used to localize the adenoma. When combined with a neck sonogram, specificity rises significantly.


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Chapter 2 Endocrinology


Treatment. Medical treatment, used if surgery is contraindicated or if serum calcium ≤11.5 mg/ dL and patient is asymptomatic, includes bisphosphonates (pamidronate).

Diabetic nephropathy. Nephropathy affects 30–40% of type 1 diabetics and 20–30% of type 2 diabetics. Hyperproliferation, proteinuria, and end-stage renal disease can develop. The pathology can be diffuse, which is more common, and lead to widening of glomerular basement membrane and mesangial thickening. Nodular pathology can occur and results in hyalinization of afferent


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The most common pattern of dyslipidemia in patients with type 2 diabetes is elevated triglyceride and decreased HDL cholesterol.


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USMLE Step 2 l Internal Medicine


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glomerular arterioles (Kimmelstiel-Wilson syndrome). Management of nephropathy involves strict control of diabetes, ACE-inhibitors, and dialysis or renal transplantation.

All diabetics should be screened for proteinuria annually. Proteinuria is detectable on a standard dipstick when the level >300 mg per 24 hours. Microalbuminuria is defined as a level 30–300 mg. All those with proteinuria should receive therapy with an ACE inhibitor or angiotensin receptor blocker. Diabetes is the most common cause of end-stage renal disease in the United States.

Diabetic retinopathy. The retina is affected, and diabetes is the leading cause of blindness in middle-aged patients. Simple/background, or proliferative (microaneurysms, hemorrhages, exudates, retinal edema) damage can occur.


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Wikimedia, Jonathan Moore


Figure 2-12. Diabetic Foot Ulcer


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Chapter 2 Endocrinology


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As with other microvascular complications, prevention of neuropathy in diabetes is by tight glycemic control. Management once it occurs depends on the type. For peripheral neuropathy, analgesics, gabapentin, pregabalin, amitriptyline, and carbamazepine are used (gabapentin and pregabalin are the best). For gastroparesis, metoclopramide or erythromycin can be used.

Erectile dysfunction is treated with sildenafil and similar drugs.

Additional Concepts. The “honeymoon” period (in IDDM patients) is an initial episode of ketoacidosis followed by a symptom-free interval during which no treatment is required. Presum- ably stress-induced epinephrine release blocks insulin secretion, causing the syndrome. In normal individuals insulin reserve is such that hormone release is adequate even in the face of stress.

The Somogyi effect is rebound hyperglycemia in the morning because of counterregulatory hormone release after an episode of hypoglycemia in the middle of the night.

The Dawn phenomenon is an early morning rise in plasma glucose secondary to a rise in counter-regulatory hormones cortisol, epinephrine, and GH requiring increased amounts of insulin to maintain euglycemia.


Hypoglycemia

Glucose is the primary energy source of the brain. Symptoms of hypoglycemia are divided into 2 groups and can occur because of excessive secretion of epinephrine, leading to sweat- ing, tremor, tachycardia, anxiety, and hunger. Hypoglycemia can also occur because of dysfunction of the CNS, leading to dizziness, headache, clouding vision, blunted mental activity, loss of fine motor skills, confusion, abnormal behavior, convulsions, and loss of consciousness. There is no uniform correlation between a given level of blood sugar and symptoms. Major symptoms in normal persons may not be seen until blood sugar is

20 mg/dL.

Classification. Postprandial hypoglycemia (reactive) can be secondary to alimentary hyperin- sulinism (after gastrectomy, gastrojejunostomy, pyloroplasty, or vagotomy), idiopathic, and galactosemia.

Fasting hypoglycemia can result from conditions in which there is an underproduction of glucose, such as hormone deficiencies (panhypopituitarism, adrenal insufficiency), enzyme defects, substrate deficiency (severe malnutrition, late pregnancy), acquired liver disease, or drugs (alcohol, propanolol, salicylates). Fasting hypoglycemia can also occur in conditions related to overutilization of glucose such as hyperinsulinism. Hyperinsulinism can occur secondary to insulinoma, exogenous insulin, sulfonylureas, drugs (quinine), endotoxic shock, and immune disease with insulin receptor antibodies. Overutilization of glucose can also occur in states in which there are appropriate insulin levels, such as extrapancreatic tumors and rare enzyme deficiencies.

Insulinoma (pancreatic B-cell tumor) can cause hypoglycemia. Ninety percent of these tumors are single and benign. Clinical findings include symptoms of subacute or chronic hypoglycemia such as blurred vision, headache, feelings of detachment, slurred speech, and weakness.

Symptoms occur in the early morning or late afternoon or after fasting or exercise.

Diagnosis. This is made by finding a serum insulin level ≥8 mg/mL in the presence of blood glucose <40 mg/dL (i.e., inappropriately high serum insulin level when glucose is low), noted either spontaneously or during a prolonged fast (72 hours). CT scan, U/S, and arteriography may also be useful in detecting the tumor(s). Management of insulinoma is by surgery, diet, and medical therapy.


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USMLE Step 2 l Internal Medicine


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Factitious hyperinsulinism is caused by self-administration of insulin or ingestion of Equal or oral sulfonylureas. It is common and exceeds the incidence of insulinomas. Most often, these patients are associated with the health professions or have access to these drugs by a diabetic member of the family. A triad of hypoglycemia, high immunoreactivity, insulin, and sup- pressed plasma C-peptide is pathognomonic of exogenous insulin administration.

Ethanol-induced hypoglycemia can also occur with prolonged starvation, when glycogen reserves become depleted in 18–24 hours and hepatic glucose output depends completely on gluconeogenesis. Ethanol at a concentration of 45 mg/dL can induce hypoglycemia by block- ing gluconeogenesis.

Table 2-6. Differential Diagnosis of Insulinoma and Factitious Hyperinsulinism

Test

Insulinoma

Exogenous Insulin

Sulfonylureas

Plasma insulin

High (usually <200

µU/mL)

Very high (usually

>1,000 µU/mL)

High

Proinsulin

Increased

Normal or low

Normal

C peptide (insulin connective peptide) 1:1

Increased

Normal or low

Increased

Insulin antibodies

Absent

+/– Present

Absent

Plasma or urine sulfonylurea

Absent

Absent

Present


Clinical Recall

Which of the following medications is contraindicated in patients with acute pulmonary edema with an ejection fraction of 25%?

  1. Glyburide

  2. Metformin

  3. Rosiglitazone

  4. Exenatide

  5. Sitagliptin


Answer: C


DISEASES OF THE ADRENAL GLAND

The adrenal gland is divided into 2 areas: the cortex and medulla. The cortex is divided into 3 areas, the outer zone (glomerulosa), which is the site of aldosterone synthesis; the central zone (fasciculata), which is the site of cortisol synthesis; and the inner zone (reticularis), which is the site of androgen biosynthesis. The disorders of hyperfunction of the gland are associated with the following specific hormones: increased cortisol is seen in Cushing syn- drome; increased aldosterone in hyperaldosteronism; and increased adrenal androgens with virilization in women.


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Chapter 2 Endocrinology


Region

Hormones Controlled by


Capsule

Zona

Glomerulosa

Aldosterone

Angiotensin II, [K+]


Zona

Fasciculata

Cortisol


and

ACTH


Zona

Reticularis

Androgens


(LH has no effect on the production

of adrenal androgens)


Medulla

Epinephrine Autonomic Nervous

System


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Figure 2-13. Adrenal Cortex Regions


Hyperfunctioning of the Gland


Cushing syndrome

Cushing syndrome is a group of clinical abnormalities caused by prolonged exposure to increased amounts of cortisol or related corticosteroids. The most common causes are exogenous, iatrogenic, and those secondary to prolonged use of glucocorticoids.

The etiology of Cushing syndrome includes adrenal hyperplasia. This can be secondary to pituitary ACTH production, which occurs in pituitary-hypothalamic dysfunction, and pituitary ACTH-producing adenomas (microadenoma, e.g., Cushing disease). ACTH- producing pituitary adenomas cause about 60–80% of Cushing cases. Adrenal hyperplasia can also be secondary to ACTH or corticotropin-releasing hormone (CRH), produced by nonen- docrine tumors (bronchogenic carcinoma, carcinoma of the thymus, pancreatic carcinoma, and bronchial adenoma). Adrenal neoplasia, such as adenoma or carcinoma, and adrenal nodular hyperplasia account for about 30% of Cushing cases. Excessive cortisol production by an autonomous adrenal tumor results in a low ACTH level. About 15% of Cushing cases are from ACTH from a source that cannot be located.

Clinical Findings. The clinical findings of Cushing syndrome include deposition of adipose tissue in characteristic sites such as upper fat, moon facies; interscapular buffalo hump; and mesenteric bed, truncal obesity. Other clinical findings include hypertension, muscle weakness, and fatigability related to mobilization of peripheral supportive tissue; osteoporosis caused by increased bone catabolism; cutaneous striae; and easy bruisability. Women may have acne, hirsutism, and oligomenorrhea or amenorrhea resulting from the increased adrenal androgen secretion. Emotional changes range from irritability or emotional lability to severe depression or confusion; even psychosis can occur as well. Glucose intolerance is common in Cushing disease, with 20% of patients having diabetes.


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USMLE Step 2 l Internal Medicine


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Cushing and glucocorticoid use are also associated with hypokalemia and leukocytosis. Hypokalemia occurs because of the mineralocorticoid effect of the steroids.

Clinically significant hypokalemia is uncommon.

Other manifestations are delayed wound healing, renal calculi from increased calcium levels, and glaucoma. Polyuria is from hyperglycemia. There is increased susceptibility to infections because neutrophils exhibit diminished function because of high glucocorticoid levels.

Diagnosis. The diagnostic tests used to establish the syndrome of cortisol excess are the 1-mg overnight dexamethasone suppression test and the 24-hour urine-free cortisol. The tests used to establish a precise etiology of the cortisol excess are the ACTH level, high-dose dexametha- sone suppression test, CT and MRI scanning, and occasionally sampling of the petrosal venous sinus, which drains out of the pituitary.

The 1-mg overnight dexamethasone suppression test is used to rule out the diagnosis of Cushing syndrome or glucocorticoid excess. If you give a milligram of dexamethasone at 11 p.m., the cortisol level at 8 a.m. should come to normal if there is the normal ability to suppress ACTH production over several hours. The problem with this test is that there can be falsely abnormal or positive tests. Any drug that increases the metabolic breakdown of dexamethasone will prevent its ability to suppress cortisol levels. Examples of drugs increasing the metabolism of dexametha- sone are phenytoin, carbamazepine, and rifampin. Stress increases glucocorticoid levels. The

  1. mg overnight dexamethasone suppression test can be falsely positive in stressful conditions such as starvation, anorexia, bulimia, alcohol withdrawal, or depression.

    An abnormality on the 1-mg overnight test should be confirmed with a 24-hour urine-free cortisol. The 24-hour urine-free cortisol is more accurate and is the gold standard for confirm- ing or excluding Cushing’s syndrome.

    A third screening test for Cushing is the midnight salivary cortisol. In normal patients, cortisol is at its lowest at midnight. In Cushing patients, cortisol is abnormally elevated at midnight.

    The precise etiology of the Cushing syndrome is established by using ACTH levels, sometimes in combination with high-dose dexamethasone suppression testing. ACTH levels are elevated with either a pituitary source of ACTH such as an adenoma or with an ectopic source. High- dose dexamethasone suppression testing can distinguish the difference. The output of a pituitary adenoma will suppress with high-dose dexamethasone. The output of an ectopic source will not suppress with high-dose dexamethasone.

    If the ACTH level is low, then the etiology is most likely from an adrenal tumor such as an adeno- ma, cancer, or from adrenal hyperplasia. When the adrenal gland is the source of increased cortisol production, there is feedback inhibition on the pituitary and the ACTH level is suppressed.

    When there is a low ACTH level, the precise etiology is confirmed with a CT scan of the adrenals.

    When there is a high ACTH level, the precise etiology is confirmed with an MRI of the pituitary looking for an adenoma or a CT scan of the chest looking for an ectopic focus.

    If neither of these shows a lesion or the MRI of the brain is equivocal, then inferior petrosal sinus sampling should be done to see if there is increased ACTH coming out of the brain.

    Single random cortisol levels are not reliable.

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The most common cause of primary hyperaldosteronism is a unilateral adrenal adenoma (70%). Bilateral hyperplasia accounts for 25–30%. Excessive black licorice ingestion can mimic this effect. Licorice has aldosterone-like qualities.


Primary Aldosteronism

Secondary Aldosteronism


Initiating event

Intravascular volume

i Na+ retention i Renin

i Intravascular volume

i Na+ retention Renin


i Aldosterone production

i Aldosterone production


Initiating event


Figure 2-15. Mechanism of Hyperaldosteronism


Clinical. Primary hyperaldosteronism is characterized by hypertension and low potassium levels. Most of the other symptoms, such as muscle weakness, polyuria, and polydipsia, are from the hypokalemia. Metabolic alkalosis occurs because aldosterone increases hydrogen ion (H+) excretion. Aldosterone causes alkalosis. Edema is uncommon with primary hyperaldosteronism because of sodium release into the urine.


Table 2-7. Clinical and Laboratory Findings in Primary and Secondary Aldosteronism


Primary Aldosteronism

Secondary Aldosteronism

Diastolic hypertension

+

Muscle weakness

+

+/–

Polyuria, polydipsia

+

+/–

Edema

+/–

Hypokalemia

+

+

Hypernatremia

+

Metabolic alkalosis

+

+

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Chapter 2 Endocrinology


Diagnosis. The preliminary screen for hyperaldosteronism is a plasma aldosterone concentra- tion (PAC) and plasma renin activity (PRA). A positive screen is a PAC/PRA ratio >20:1 and a PAC >15. To confirm hyperaldosteronism, an NaCl challenge is required. This can be via normal saline, NaCl tabs, or fludrocortisone. After an NaCl challenge, PAC should be sup- pressed as in a normal individual. If PAC is still elevated, this confirms the diagnosis.

Management. Adrenal adenomas are removed surgically. Bilateral hyperplasia is treated with spironolactone, which blocks aldosterone.

Bartter Syndrome. The exception of secondary hyperaldosteronism without edema or hypertension is Bartter syndrome. Bartter syndrome is caused by a defect in the loop of Henle in which it loses NaCl. This is due to a defect in the Na-K-2Cl cotransporter. This is like having a furosemide-secreting tumor.

In Bartter syndrome there is juxtaglomerular hyperplasia, normal to low blood pressure, no edema, severe hypokalemic alkalosis, defect in renal conservation of sodium or chloride, and renal loss of sodium, which stimulates renin secretion and aldosterone production.


Syndromes of adrenal androgen excess

Syndromes of adrenal androgen excess result from excess production of dehydroepiandros- terone (DHEA) and androstenedione, which are converted to testosterone in extraglandular tissues. The elevated testosterone accounts for most androgenic effects.

Clinical Signs and Symptoms. Hirsutism, oligomenorrhea, acne, and virilization. Etiology includes congenital adrenal hyperplasia, adrenal adenomas (rare), and adrenal carcinomas.


Congenital adrenal hyperplasia

Congenital adrenal hyperplasia (CAH) is the most common adrenal disorder of infancy and childhood. It is associated with increased adrenal androgen production because of enzymatic defects. CAH arises from autosomal recessive mutations, which produce deficiencies of enzymes necessary for the synthesis of cortisol.

Common Enzymatic Defects Associated with CAH. Enzymatic defects include C-21 hydroxylase deficiency in 95% of all cases. C-21 hydroxylase deficiency is associated with reduction in aldosterone secretion in one-third of patients. Adrenal virilization occurs with or without an associated salt-losing tendency, owing to aldosterone deficiency, which leads to hyponatremia, hyperkalemia, dehydration, and hypotension.

Patients are female at birth with ambiguous external genitalia (female pseudohermaphroditism), enlarged clitoris, and partial or complete fusion of the labia. Postnatally CAH is associated with virilization. Patients may be male at birth with macrogenitosomia; postnatally this is associated with precocious puberty.

    1. hydroxylase deficiency can also occur. The mineralocorticoid manifestations in C-11 deficiency can be ‘biphasic.’ In early infancy, despite having excessive mineralocorticoid hormones, patients sometimes present with relative ‘salt wasting’ (aldosterone deficiency). This is because some infants have inefficient salt conservation as well as immature aldosterone production.

      During this phase, infants can present with hypotension and hyperkalemia (very similar to 21 hydroxylase deficiency). Later in life (childhood and adulthood), there is better ability to hold onto salt, so the patient develops the typical C-11 deficiency syndrome: hypertension and hypokalemia.


      Note

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      The ‘biphasic’ presentation is rare. When you think about 11 deficiency, think mineralocorticoid excess (hypertension and

      hypokalemia) with low cortisol production (remember you need C-11 for the final step in converting to cortisol).


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      USMLE Step 2 l Internal Medicine


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        1. hydroxylase deficiency can occur as well, and is characterized by hypogonadism, hypoka- lemia, and hypertension resulting from increased production of 11-deoxycorticosterone.

          Diagnosis. CAH should be considered in all infants exhibiting failure to thrive, especially those with episodes of acute adrenal insufficiency, salt wasting, or hypertension. The most useful measurements are of serum testosterone, androstenedione, dehydroepiandrosterone, 17-hydroxyprogesterone, urinary 17-ketosteroid, and pregnanetriol.

          Management. Treatment is glucocorticoid (hydrocortisone) replacement.


          Clinical Recall

          An elderly, obese, diabetic patient comes to the clinic with LDL levels of 150 mg/dL. Which medication should be given at this time?

          1. Niacin

          2. Atorvastatin

          3. Gemfibrozil

          4. Lisinopril

          5. Gabapentin


      Answer: B


      Hypofunctioning of the Gland


      Adrenal insufficiency

      Adrenal insufficiency can be divided into primary adrenocorticoid insufficiency (Addison disease) and secondary failure in the elaboration of ACTH.

      Primary adrenocortical insufficiency is a slow, usually progressive disease due to adrenocorti- coid hypofunction. The etiology can be secondary to anatomic destruction of the gland (chronic and acute). Idiopathic atrophy is the most common cause of anatomic destruction, and autoimmune mechanisms are probably responsible. Autoimmune destruction accounts for 80% of cases. Anatomic destruction can also be secondary to surgical removal, infection (TB, fungal, cytomegalovirus), hemorrhagic, trauma, and metastatic invasion. Metabolic failure in hormone production can also lead to Addison disease and can be secondary to CAH, enzyme inhibitors, and cytotoxic agents (mitotane).

      Clinical Findings. The clinical findings in Addison disease include weakness, paresthesias, cramping, intolerance to stress, and personality changes such as irritability and restlessness. Chronic disease is characterized by a small heart, weight loss, and sparse axillary hair. Hyper- pigmentation of the skin can occur and appears as diffuse brown, tan, or bronze darkening of both exposed and unexposed body parts. Arterial hypotension is seen and is often orthostatic owing to lack of effect of cortisol on vascular tone. Abnormalities of GI function are found, and symptoms vary from mild anorexia with weight loss to nausea, vomiting, diarrhea, and abdominal pain. Acute Addisonian crisis is characterized by fever and hypotension. A low sodium with a high potassium level and mild acidosis are also present.



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      Diagnosis. The diagnosis of Addison disease is made through rapid ACTH administration and measurement of cortisol. Laboratory findings include white blood cell count with moderate neutropenia, lymphocytosis, and eosinophilia; elevated serum potassium and urea nitrogen; low sodium; low blood glucose; and morning low plasma cortisol.

      The definitive diagnosis is the cosyntropin or ACTH stimulation test. A cortisol level is obtained before and after administering ACTH. A normal person should show a brisk rise in cortisol level after ACTH administration.

      Differences between primary and secondary adrenal insufficiency:

      Curative surgical removal of the pheochromocytoma is performed only after BP has been stabilized; during surgery, IV phentolamine—a rapid-acting alpha-adrenergic antagonist—is used for controlling BP.


      DISEASES OF THE TESTES, HYPOGONADISM

      In hypogonadism there is decreased function of the testes or ovaries, resulting in the absence or impairment of secondary sexual characteristics and infertility.


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      Note

      Males affected by Klinefelter syndrome have a 20 × increased risk of breast

      cancer .


Answer: E



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Learning Objectives


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EVALUATING A PATIENT WITH ARTHRITIS

When a patient presents with joint swelling, a differential diagnosis is generated based on the answers to the following questions:

  1. What is the distribution of joint involvement and how many joints are involved?

    Polyarticular symmetric involvement is characteristically seen with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), parvovirus B19, and hepatitis B.

    Monoarticular arthritis is consistent with osteoarthritis (OA), crystal-induced arthritis (gout, pseudogout), septic arthritis (gonococcus), trauma, and hemarthrosis.

    Migratory arthropathy (inflammation and pain migrate from joint to joint while the previous involved joints improve) is caused by rheumatic fever, disseminated gonococcal infection, and Lyme disease.


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    Oligoarticular asymmetric arthritis is common with the spondyloarthropathies (ankylosing spondylitis) and OA involving the small joint of the upper extremities. It is rarely in the presentation of polyarticular gout.

  2. Are the symptoms acute or chronic?

    OA is a chronic disease; patients have symptoms for months to years. With septic arthritis or crystal-induced arthropathy, patients have short-lived symptoms, i.e., only a few days.

  3. Does the patient have systemic symptoms (beyond the arthritis)?

    SLE presents with lung (pleural effusions), kidney (proteinuria and renal failure), CNS (vasculitis, strokes, and change in personality), skin (malar and photosensitivity rash), and hematologic (immune-mediated anemia, thrombocytopenia) manifestations.

    Sjögren syndrome has keratoconjunctivitis sicca (dry eyes/mouth) and parotid enlargement. Systemic sclerosis has skin involvement and Raynaud phenomenon.

    Wegener granulomatosis presents with upper respiratory (sinusitis and rhinitis), lower respiratory (lung nodules and hemoptysis), and renal (necrotizing glomerulonephritis) involvement.

    OA presents with an absence of systemic symptoms.

  4. Is there evidence of joint inflammation?

    Evidence of joint inflammation includes joint stiffness in the morning >1 hour, joint erythema and warmth, and elevated erythrocyte sedimentation rate (ESR) and C-reactive protein. RA would produce inflammation, while OA would not.

    Do not go further into a history unless you have answered these 4 questions. Examples


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Table 3-1. Synovial Fluid Analysis in Rheumatologic Disease


Disease

WBCs

Crystals/Polarization

DJD

<2,000

Negative traumatic

Inflammatory

5,000–50,000

Gout: needle-shaped, negative birefringent

Pseudogout (CPPD): rhomboid-shaped, positive birefringent

Septic

>50,000

Negative (Gram stain and culture usually negative for GC but positive in Staph, strep, and gram-negatives)


There are a few exceptions to the above:

Subsets of ANAs are associated with specific autoimmune diseases and thus used to further diagnose those diseases. For example, anti ds-DNA and anti-SM antibodies are found in patients with SLE; anti-histone antibodies are found in patients with drug-induced lupus.



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Clinical Correlate Overall, >95% of SLE patients have positive ANA test results,

making a negative ANA result

a good rule-out test for SLE.

Interpret a positive ANA test in the context of the clinical symptoms:

  1. ray abnormalities and nodules are not needed for a diagnosis of RA.

    Criteria. RA is a chronic inflammatory symmetric arthropathy. There needs to be involve- ment of multiple joints, but some joints are never involved in RA:


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Gastroesophageal Reflux Disease

A 32-year-old man comes to the emergency department for substernal chest pain of 2 hours’ duration. He says that he sometimes gets this pain while lying in bed at night. He is otherwise free of symptoms, except for a nonproductive cough that he has had for the past month or so. Physical examination is unremarkable. ECG is normal. He is given sublingual nitroglycerin and notes that his chest discomfort is worsened.


Gastroesophageal reflux disease (GERD) is caused by the abnormal flow of the acid gastric contents backward from the stomach up into the esophagus. The lower esophageal sphincter (LES) is not a true anatomic sphincter (it cannot be found in a cadaver); it is created by the different response of the smooth muscle cells in the distal esophagus.

A number of factors can cause decreased tone or loosening of this sphincter.

24-hour pH monitoring is not needed. If EGD is normal, do ambulatory 24-hour pH monitoring (while off the PPI) and if results are consistent with GERD, do Nissen fundoplication.

In clear cases of epigastric pain going under the sternum and associated with a respiratory complaint or bad taste in the mouth, initiate therapy immediately with antisecretory medica- tions such as PPIs.


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There is no point in treating

  1. pylori without evidence of disease such as gastritis or ulcer disease.


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    Note

    In patients with chronic cough (8 weeks), symptoms typical of GERD (heartburn, cough

    that is worse after a large meal), and negative chest

    1. ray, initiate a PPI as the next most appropriate step.

      Treatment. Treatment is a PPI and lifestyle modification (avoid nicotine/alcohol/caffeine/ chocolate/late-night meals and elevate the head of the bed 6–8 inches with blocks to keep acid in the stomach)

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    Zollinger-Ellison syndrome is the excessive production and release of gastrin from the pancreas. Somatostatin is the counterbalance to this system, inhibiting the release of gastrin and histamine, as well as having a direct inhibitory effect on the production of acid from the parietal cells. Secretin is released from the S cells of the duodenal lining. The main stimulant to the release of secretin is the presence of acid in the duodenum. Secretin inhibits the produc- tion of gastrin, as well as stimulates pancreatic and biliary bicarbonate production and release.

    The most common cause of ulcer disease is Helicobacter pylori followed by the use of NSAIDs; 80–90% of duodenal ulcers and 70–80% of gastric ulcers are associated with

    1. pylori. Overall, 10–20% of ulcers are idiopathic, and no clear etiology is ever identified.

      Clinical Presentation. The most common presentation of ulcer disease is midepigastric pain. There is no definite way to distinguish between duodenal and gastric ulcer simply by symp- toms. Gastric ulcer is often associated with pain on eating (frequently leading to weight loss), while duodenal ulcer is thought to be relieved by eating. However, these associations are only rough approximations, and endoscopy is still required for a definite diagnosis.

      Tenderness of the abdomen is unusual with ulcer disease. More than 80% are not associated with abdominal tenderness in the absence of a perforation. Nausea and vomiting are occasion- ally found with both of them.

      Diagnosis. Ulcer disease is best diagnosed with upper endoscopy. Barium studies are inferior.


Clinical Recall

A 36-year-old man complains of intermittent, worsening epigastric pain radiating to the back for the past 3 months. The patient claims to drink alcohol only during business trips but admits to blacking out several times from too much alcohol. Which of the following is the most likely cause of his symptoms?

  1. Barrett’s esophagus

  2. Candida esophagitis

  3. Gastritis

  4. GERD

  5. Pancreatitis


Answer: E


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Note

Sclerosing cholangitis does not correlate to disease activity.


Note

Always check stool studies, especially C. difficile toxin during a flare.


Note

Check thiopurine methyltransferase level before starting azathioprine and

  1. mercaptopurine; they are contraindicated in 1 in 300 patients who lack this enzyme and are at high risk for drug toxicity. Do not give allopurinol or febuxostat with these drugs (they are also metabolized by

    INFLAMMATORY BOWEL DISEASE

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    Inflammatory bowel disease (IBD) describes 2 disease entities: Crohn’s disease (CD) and ulcerative colitis (UC). They can be discussed simultaneously because of the large degree of overlap in terms of presentation, testing, and treatment.

Treatment. Therapy is divided into active and maintenance.

xanthine oxidase).


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Table 4-2. Treatment of CD versus UC

Crohn’s Disease

Ulcerative Colitis

5-ASAs are often ineffective

Depends on severity of disease

Mild:

For active disease prednisone or budesonide

For maintenance azathioprine and 6-mercaptopurine

Mild: 4 bowel movements/day, mild bleeding, normal labs

Mesalamine or sulfasalazine (causes reversible infertility in men and leukopenia by its sulfapyridine group)

Moderate: fever, weight loss, anemia, abdominal pain, nausea/vomiting

For active steroids

For maintenance azathioprine and 6-mercaptopurine or methotrexate

For remission anti-TNF antibodies

Moderate: 4–6 bowel movements/day For active disease prednisone

For remission budesonide

For long-term maintenance azathioprine and 6-mercapto- purine (associated with drug-induced pancreatitis) to try to keep patients off steroids

Severe to fulminant: high fever, vomiting, rebound, obstruction

For acute exacerbations, IV steroids or anti-TNF (better choice), possible surgery

Severe: >6 bowel movements/day, bleeding, fever, tachycardia, ESR >30 mm/h, anemia

For acute exacerbations that fail steroids, and for mainte- nance if azathioprine and 6-mercaptopurine fail or are contraindicated, IV steroids followed by anti-TNF-alfa (infliximab, adalimumab, golimumab)

Fistula: anti-TNF

For induction and maintenance anti-TNF antibodies (infliximab, adalimumab, certolizumab); if anti-TNF fails (can cause PML so check JC virus antibodies first) natali- zumab (a monoclonal antibody to integrin-alfa-4 on leukocytes)


For those with perianal disease ciprofloxacin and metroni- dazole

For those who form fistulae or have disease refractory to other therapies infliximab


Surgery is not very effective; disease tends to reoccur at the site of anastomosis

Surgery is curative; almost 60% of patients will require surgery within 5 years after diagnosis due to refractory symptoms or severe disease

For both, start screening colonoscopy 8–10 years after diagnosis and repeat every 1–2 years.


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Note

Check PPD, HBV, HCV prior to initiating anti-TNF agent.


Note

With management of diarrhea, determine when to admit the patient and when to use IV fluids and antibiotics. That is more important than determining the precise causative agent.

DIARRHEA

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Diarrhea is increased frequency or volume of stool per day (alternatively, it can be defined as few stools per day but with watery consistency). The most common causes include an infec- tious, antibiotic-associated, or lactose-intolerance etiology, irritable bowel syndrome, and carcinoid syndrome.

The patient is often hypotensive, febrile, and experiencing abdominal pain.

Diagnosis. The first step in the evaluation of diarrhea is to see if there is hypovolemia as defined as hypotension or orthostasis. This is more important than determining specific etiology because the patient could die while waiting for the results to come back.

Treatment. No matter the etiology, if the patient is hypotensive, febrile, and having abdominal pain, admit as inpatient and give IV fluids and antibiotics. Blood in the stool is especially serious, and is probably the single strongest indication for the use of antibiotics, such as ciprofloxacin.


Infectious Diarrhea

The majority of acute diarrhea is viral and self-limited. Clostridium difficile toxin and stool

Giardia-antigen testing are done when there are clues to these diagnoses in the history.

With bacterial diarrhea, the most common causes are Campylobacter and Salmonella, espe- cially in patients with sickle cell and achlorhydria. A definitive determination of the etiology can only be made with a stool culture.



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Table 4-3. Clues to the Diagnosis of Infectious Diarrhea Prior to Results of Culture

Causative Agent

Patient Symptoms or History

Additional Comments

Bacillus cereus

  • Ingestion of refried Chinese food and the spores from Bacillus that it contains.

  • Vomiting is prominent

  • Blood is never present

Short incubation period (1–6 hours)

Campylobacter

Reactive arthritis, Guillain-Barré syndrome

Most common cause of bacterial gastroenteritis

Cryptosporidia, Isospora

Found in HIV-positive patients with <100/mm3

CD4 cells

E. coli 0157:H7

Ingestion of contaminated hamburger meat; the organism can release a Shiga toxin, provoking hemolytic uremic syndrome

Hemolytic uremic syndrome happens when organism dies; that is why antibiotics are contrain- dicated. Platelet transfusion is also contraindi- cated, even if platelet count is low because new platelets may only make it worse

Giardia

If not eradicated, can simulate celiac disease in terms of causing fat and vitamin malabsorption

Salmonella

Ingestion of chicken and eggs, dairy products

Scombroid

Ingestion of contaminated fish; almost immediate vomiting, diarrhea, flushing, and wheezing

Organisms invade, producing and then releasing histamine into the flesh of fish, such as tuna, mahi mahi, and mackerel

Shigella, Yersinia

No clues strong enough to point to etiology until the results of stool culture are known

Yersinia can mimic appendicitis. Also common in people with iron overload, e.g., hemochromatosis.

Vibrio parahaemolyticus

Ingestion of raw shellfish, such as mussels clams

Typically presents as severe systemic gastroenteri- tis in patients with underlying disease (esp. chronic liver disease)

Vibrio vulnificus

Ingestion of raw shellfish (particularly affects those with underlying liver disease)

Skin bullae

Typically presents as severe systemic gastroenteri- tis in patients with underlying disease (esp. chronic liver disease or disorders of iron metabolism)

Viral

Children in day-care centers; absence of blood and white cells

No systemic manifestation

Staphylococcus aureus

  • Ingestion of dairy products, eggs, salads

  • Upper GI symptoms (nausea/vomiting) predominate; rarely diarrhea

Short incubation period (1–6 hours)

Ciguatera-toxin

Ingestion of large reef fish (grouper, red snapper, barracuda); 2–6 hours after inges- tion, neurological symptoms leading to paresthesia, weakness, reversal of hot/cold



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Antibiotic- and C. difficile-Associated Diarrhea

Antibiotic-associated diarrhea (AAD) is a benign, self-limited diarrhea following the use of antimi- crobials. Typically, no pathogens are identified; the diarrhea is caused by changes in the composi- tion and function of the intestinal flora, as well as increased motility (common with agents like erythromycin). Most patients respond to supportive measures and discontinuation of antibiotics.

Clostridium difficile-associated diarrhea (C. diff) refers to a spectrum of diarrheal illnesses caused by the toxins produced by C. diff, including severe colitis with or without the presence of pseudomembranes. (For exam purposes, this discussion will focus on C. diff.)

Pathogenesis. Any antibiotic can lead to diarrhea with C. diff, although antibiotics that are broad spectrum are more likely to do so. Clindamycin may have one of the highest frequencies of association, as do fluoroquinolones and cephalosporins.

  1. diff diarrhea is largely a nosocomial disease and is the most frequent cause of diarrhea in hospitalized patients. It occurs infrequently in the outpatient setting, other than in patients confined to nursing homes. Research suggests a significant association between C. difficile and the use of PPIs.

    Clinical Presentation and Diagnosis. The clinical manifestations of C. diff may vary from mild diarrhea to fulminant colitis. If a patient develops diarrhea several days to weeks (even up to 8 weeks) after using antibiotics, evaluate for C. diff. Marked leukocytosis and systemic symptoms are evident in severe cases.


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Note

Do not use fidaxomicin for the first episode of C. diff colitis.

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Diagnosis. There is no specific diagnostic test for IBS. The first step is to exclude lactose intolerance, IBD, celiac disease, carcinoid, Giardia infection, and anatomic defects of the bowel as the cause.

The diagnostic criteria, called Rome criteria, must occur for at least 3 months:

Do not use alosetron due to risk of ischemic colitis.


Carcinoid Syndrome

Carcinoid syndrome describes tumors of the neuroendocrine system. They are most often located in the appendix and ileum. By definition carcinoid syndrome implies metastatic disease (except for bronchial carcinoids). Until there is an enormous tumor burden, the liver is able to neutralize all of the serotonin released by the carcinoid in the bowel. This usually does not happen until the metabolic capacity of the liver has been overwhelmed by metastatic disease.

Bronchial carcinoids are rare but highly symptomatic because the serotonin produced is released directly into the circulation without being detoxified in the liver.

Clinical Presentation. Carcinoid syndrome presents with diarrhea, flushing, tachycardia, and hypotension. A rash may develop from niacin deficiency, a direct result of the carcinoid.

Serotonin and niacin are both produced from tryptophan, so if there is an overproduction of serotonin, a tryptophan deficiency and thus a niacin deficiency, will result. Endocardial fibrosis also occurs because of a constant exposure of the right side of the heart to the serotonin. This leads to tricuspid insufficiency and pulmonic stenosis.

Diagnosis. The diagnosis is confirmed with urinary 5-hydroxyindolacetic acid level (5-HIAA).

Treatment. Therapy is generally based on controlling the diarrhea with octreotide, a soma- tostatin analog. Very few carcinoids are sufficiently localized to be amenable to surgical resection. If a tumor does happen to be localized, then it should be resected. This is most often possible with bronchial carcinoid. Surgery is also used to relieve obstruction of the bowel.


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Clinical Pearl Antibodies Seen in Celiac Disease

If CT does not show calcifications, get MRCP to detect abnormal pancreatic ducts.

For young adults with chronic pancreatitis, work up for cystic fibrosis (especially if there is recurrent pneumonia, sinusitis, and infertility).

Suspect tropical sprue when there is a history of being in a tropical country, and Whipple disease (very rare) if there is dementia (10%), arthralgia (80%), and ophthalmoplegia.

Treatment. Treatment includes pancreatic enzymes; pain control with NSAID/acetamino- phen, tramadol (may cause hypoglycemia), tricyclic antidepressant, gabapentin, or pregabalin; insulin (required for diabetics, as it mimics type 1 diabetes due to destruction of beta cells). Do not use narcotics for pain control.


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Celiac Sprue

Celiac sprue is secondary to ingestion of wheat, gluten, or related rye and barley proteins. Patients present with the following:

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In chronic pancreatitis, lipase and amylase are usually normal due to a burnt out pancreas.


Clinical Correlate

Do not let the lack of diarrhea and weight loss keep you from considering celiac. Test for celiac in anyone with unexplained elevation in LFTs or multiple vitamin deficiencies.

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Clinical Recall

A 22-year-old woman complains of intermittent bloating and diarrhea for the past 3 months. Her symptoms are relieved when she avoids her morning coffee and ice cream. On diagnostic testing, her blood and stool tests were within normal limits except for a mild elevation in stool osmolality. What is the most likely cause of her symptoms?

  1. Celiac sprue

  2. Carcinoid syndrome

  3. Irritable bowel syndrome

  4. Lactose intolerance

  5. Whipple’s disease


Answer: D


DIVERTICULAR DISEASE

In diverticular disease, small bulges or pockets develop in the lining of the intestine. They often develop where the muscles are weakest, e.g., where penetrating vessels cross through muscle.


Diverticulosis

Diverticulosis is so common in older populations throughout the Western world (50% of persons age >50, with higher rates in older populations) that it is almost considered a normal part of aging. The cause of diverticulosis is believed to a lack of fiber in the diet to give bulk to stool. There is a subsequent rise in intracolonic pressure, leading to outpocketing of the colon.

Clinical Presentation. Most of the time, patients are asymptomatic. When symptoms do exist, they are typically left lower quadrant abdominal pain that is colicky in nature.

Diverticulosis is diagnosed with colonoscopy. Endoscopy is superior to barium study, particu- larly when bleeding is present. Diverticula are more common on the left in the sigmoid, but bleeding occurs more often from diverticula on the right because of thinner mucosa and more fragile blood vessels. When bleeding occurs from diverticula, it is painless.

Treatment. Treatment is an increased-fiber diet, as is found in bran, bulking agents such as psyllium husks, and soluble fiber supplements.


Diverticulitis

Diverticulitis occurs when one of the bulges or pockets (diverticula) becomes infected. This can occur when the diverticular entrance in the colon becomes blocked, perhaps by nuts or corn.

Diverticulitis is distinguished from uninfected diverticula by the presence of fever, tender- ness, more intense pain, and elevated white blood cell count.

Diagnosis is confirmed with CT scan. Barium study and endoscopy are contraindicated because there is a slightly higher risk of perforation.


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Treatment. Diverticulitis is treated with antibiotics such as ciprofloxacin and metronidazole. The other choices are ampicillin/sulbactam, piperacillin/tazobactam, or combined cefotetan or cefoxitin with gentamicin. Mild disease can be treated with oral antibiotics such as amoxicil- lin/clavulanic acid. Do colonoscopy several weeks after recovery to evaluate.


CONSTIPATION

A 72-year-old woman has a history of upper GI tract bleed and iron-deficiency anemia, for which she has recently been started on oral ferrous sulfate iron replacement. She also has a history of diabetes with peripheral neuropathy, for which she takes amitriptyline. She has untreated hypothyroidism, but is treated for hypertension with nifedipine. Currently, she has constipation, and when the stool does pass, it is very dark in color, almost black.


The most common cause of constipation is lack of dietary fiber and insufficient fluid intake. Calcium-channel blockers, oral ferrous sulfate, hypothyroidism, opiate analgesics, and medi- cations with anticholinergic effects such as the tricyclic antidepressants all cause constipation. In the patient above, the most likely cause of the constipation is the ferrous sulfate.

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Diagnosis. Colonoscopy is the most accurate diagnostic test. Sigmoidoscopy will reach the lesion only within the distal 60 cm of the colon. If the lesion is in the distal area then the sigmoidoscopy will be equally sensitive as colonoscopy, but only 60% of cancers occur there. Barium study is not as accurate as colonoscopy, nor can you biopsy.

Treatment. Treatment depends on the stage of disease and extent of its spread.

Patients with this syndrome are also at increased risk for ovarian and endometrial cancer (up to 30%).

Screening. Start screening at age 25 and undergo colonoscopy every 1–2 years.


Hereditary Polyposis Syndromes

Familial adenomatous polyposis has a very clear genetic defect. The adenomatous polyposis coli gene (APC) confers 100% penetrance for the development of adenoma by age 35 and of colon cancer by age 50. Polyps can be found as early as age 25. Start screening at age 12 and do flexible sigmoidoscopy every 1–2 years. As soon as polyps are found, perform a colectomy; a new rectum should be made from the terminal ileum.

By contrast, juvenile polyposis syndrome confers about a 10% risk of colon cancer. There are only a few dozen polyps, as opposed to the thousands of polyps found in those with familial polyposis. In addition, the polyps of the juvenile polyposis syndrome are hamartomas, not adenomas. Hamartomas confer very little risk of developing into cancer. There is no specific recommendation for screening.

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Cowden syndrome is another polyposis syndrome with hamartomas that gives only a slightly increased risk of cancer compared with the general population. These polyposis syndromes can present with rectal bleeding in a child.


Other Polyposis and Colon Cancer Syndromes

Gardner syndrome is the association of colon cancer with multiple, soft-tissue tumors, such as osteomas, lipomas, cysts, and fibrosarcomas. Osteomas are frequently found on the mandible. If osteomas are found as an incidental finding on x-ray, do a colonoscopy.

Peutz-Jeghers syndrome is the association of hamartomatous polyps in the large and small intestine with hyperpigmented spots. These are melanotic spots on the lips, buccal mucosa, and skin. The risk of cancer is slightly increased above the general population. Most common presentation is with abdominal pain due to intussusception/bowel obstruction.

Turcot syndrome is simply the association of colon cancer with central nervous system malignancies.

Screening. There is no recommendation for increased cancer screening for any of these syndromes; they are not common enough to warrant a clear recommendation for uniform early screening. There is an association of endocarditis from Streptococcus bovis with colon cancer, so if a patient has endocarditis from S. bovis, colonoscopy should be performed.


GASTROINTESTINAL BLEEDING

A 72-year-old man with a history of aortic stenosis is brought to the emergency department with red/black stool several times today. His blood pressure is 94/60 mm Hg and pulse 110/min.


The first thing to consider for a patient with GI bleed is the treatment, not the etiology.


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If osteomas are seen as an incidental finding on x-ray, perform a colonoscopy.


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Note

In >80% of cases, GI bleeding will resolve spontaneously with supportive management, irrespective of etiology.

Orthostasis is defined as a >10-point rise in pulse when the patient goes from the supine to the standing or sitting position. It is also defined as a >20-point drop in systolic blood pressure on a change in position. There should be at least a minute in between the position change and the measurement of the pulse and blood pressure to allow time for the normal autonomic dis- charge to accommodate to the position change.

Orthostasis is when the rise in pulse or drop in blood pressure persists after the position has been changed. It indicates a 15–20% blood loss. The measurement of orthostatic changes is not necessary in the patient described in this case because a pulse >100/min or a systolic blood pressure <100/min already indicates a >30% blood loss.

Diagnosis. Endoscopy is the most accurate test to determine the etiology of both upper and lower GI bleed. Barium study is always less accurate. Should biopsy be needed, an endoscopy must be performed.

Treatment. The most important step in the initial management of severe GI bleeding is to begin fluid resuscitation with normal saline or Ringer’s lactate. A complete blood count, pro- thrombin time, and type and crossmatch should be done, but if the patient is having a high vol- ume bleed as in the patient above, never wait for the test results to begin fluid resuscitation.

Clinical Presentation. The classic presentation of acute pancreatitis is midepigastric pain with tenderness, nausea, and vomiting. The pain typically radiates straight through to the back. When


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extremely severe, pancreatitis can mimic many of the features of septic shock, with fever, hypotension, respiratory distress from ARDS, elevation of white cell count, and a rigid abdomen.

Diagnosis. To diagnose, there must be 2 of the following 3 features:

Note

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Signs of Severe Necrotizing Pancreatitis

Cullen sign: blue discoloration around umbilicus due to hemoperitoneum

Turner’s sign: bluish purple discoloration of the flanks tissue catabolism of Hb.


Note

IV fluid intake in large volumes is the most important management of acute pancreatitis; it must be given in the first 12–24 hours.


Note

Other complications of pancreatitis include:


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Treatment. Steroids are used.


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LIVER DISEASE AND CIRRHOSIS

Cirrhosis develops when there is chronic and severe inflammation of the liver for an extended period of time. The regenerative capacity of the liver is enormous; however, over a long time, fibrosis will develop. And when at least 70–80% of liver function has been lost, the synthetic capacity of the liver is diminished.

In the United States the most common cause of cirrhosis is alcohol. Other causes include primary biliary cirrhosis, sclerosing cholangitis, alpha-1 antitrypsin deficiency, hemochroma- tosis, and Wilson disease.

The complications of cirrhosis are due to portal hypertension. Portal hypertension develops because of mechanical factors of fibrosis and regenerative liver nodules, as well as increased intrahepatic vascular resistance in increased portal inflow. The high pressure in the portal vein is decompressed through collateral portosystemic shunts that occur in the esophagus and the stomach.

Clinical Presentation. Despite the etiology, all forms of cirrhosis have the following features:

All of the clotting factors are made in the liver (except factor VIII and von Willebrand factor, made by endothelial cells). If factor VIII is low in addition to other factors, it is not liver disease—think disseminated intravascular coagulation (DIC), which is made in the vascular endothelial cells.

Ascites is the result of portal hypertension. A paracentesis is a sample of the ascitic fluid obtained by needle through the anterior abdominal wall. A paracentesis is used to exclude infection, as well as to determine the etiology of the ascites if it is not clear from the history.

Spontaneous bacterial peritonitis (SBP) is an idiopathic infection of ascites. The Gram stain is rarely positive because the density of microorganisms is so low. Although culture of the fluid is the most specific test, do not wait for the results to make a decision as to whether to give

antibiotics. The presence of >250/mm3 neutrophils are the criteria to determine the presence

of infection. Cefotaxime or ceftriaxone is the drug of choice for SBP, and albumin infusion

will decrease the risk of hepatorenal syndrome.


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While alcohol is the most common cause of cirrhosis in the United States, the most common reason to need a liver transplant is chronic hepatitis C.


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Note

Although a culture of the ascitic fluid is the most specific test for SBP, do not wait for culture results when considering antibiotics.


Clinical Pearl Remember to subtract the lower number (ascites

albumin) from the higher

number (serum albumin) when calculating SAAG.


Note

For HCC, do U/S screening every 6 months.

Once a patient has SBP, the risk of recurrence is 70% per year. Therefore, treat the patient with norfloxacin or ciprofloxacin daily (indefinitely) to prevent recurrence. Also, all beta-blockers must be stopped due to increased mortality.


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Wikipedia, James Heilman, MD


Figure 4-4. Ascites


Serum-Ascites Albumin Gradient. Normally, the ascitic fluid albumin level is less than the serum level. The difference between them is referred to as the serum-ascites albumin gradient (SAAG). Total protein in the ascites fluid must also be checked.

When SAAG ≥1.1, portal hypertension, the cause of ascites is increased hydrostatic pressure. The ascites total protein will tell you the cause of the elevated hydrostatic pressure.

Treatment. There is no specific therapy to reverse cirrhosis; one can only manage the complications and treat the underlying causes. (A complication to consider is hepatocellular carcinoma.) Edema and fluid overload in third spaces, such as ascites, are managed with diuretics (spironolactone most useful in cirrhosis). That is because cirrhotics have intravascular volume depletion, producing a high aldosterone state (secondary hyperaldosteronism). Furosemide is commonly added after spironolactone to increase volume removal. Giving furosemide without spironolactone will lead to hypokalemia, which can cause encephalopathy.


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Propranolol is used to prevent bleeding in portal hypertension and varices. Discontinue after SBP, refractory ascites, or hypotension.

Encephalopathy is managed with lactulose, a nonabsorbed disaccharide that bacteria metabo- lize in the colon, making it more acidic. This converts the NH3 to NH4+, or ammonia to ammonium. Ammonium is not absorbed very well, and that leads to an overall increased excretion of ammonia from the body.

If patient is not responsive, add rifaximin, an RNA polymerase blocker not absorbed which changes the flora of the GI tract. Neomycin is not used for encephalopathy due to renal toxicity.

Hepatorenal syndrome is diagnosed by the following:

Treat with midodrine, octreotide and albumin (must give for 48 hours first to rule out pre- renal). If it fails, perform liver transplant.

Although vitamin K is often given because of the elevated prothrombin time, it is not effective because the liver is unable to synthesize clotting factors regardless of how much vitamin K is present.


Primary Biliary Cirrhosis

Primary biliary cirrhosis is an idiopathic autoimmune disorder that is often seen in middle- aged women. Bilirubin does not elevate until the disease is extremely far advanced (5–10 years). There is a strong association with other autoimmune diseases, such as Sjögren syn- drome, rheumatoid arthritis, and scleroderma.

Clinical Presentation. The most common symptoms are fatigue and pruritus. At least 30% of patients are asymptomatic but are found to have an elevated alkaline phosphatase when measured for other reasons. Osteoporosis and hypothyroidism are found in 20–30% of patients.

Diagnosis. The transaminases are often normal. The most common abnormality is elevated alkaline phosphatase and gamma glutamyl transpeptidase (GGTP). Total IgM levels are also elevated. The most specific blood test is the antimitochondrial antibody.

Biopsy is always the best way to diagnose liver disease. It is the only test more specific than antimitochondrial antibodies.

Treatment. There is no specific therapy for primary biliary cirrhosis. Steroids will not help. Ur- sodeoxycholic acid is primary treatment. Cholestyramine will help with the pruritus, as will ultraviolet light. Liver transplant for late stage PBC may also be considered.


Note

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Give octreotide during a bleed, then band. Give propranolol after the bleed to prevent another bleed.


Note

In a patient with ascites, stop ACE-I, ARBs, and NSAIDs.



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Note

Primary sclerosis cholangitis is the only chronic liver disease in which a liver biopsy is not the most accurate test.


Note

Ferritin is elevated in liver disease and alcoholics.

Transferrin saturation is the best screening test; if it is negative, diagnosis is not hemochromatosis.

Primary Sclerosis Cholangitis

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Primary sclerosis cholangitis is an idiopathic disorder of the biliary system most commonly associated with inflammatory bowel disease (IBD). Although it is more often found with ulcerative colitis, it can also occur with Crohn’s disease. Cancer of the biliary system can develop in 15% of patients from the chronic inflammation.

Clinical Presentation and Diagnosis. The presentation and general lab tests are typically the same as those for primary biliary cirrhosis, except that the antimitochondrial antibody test will be negative. The most specific test for primary sclerosis cholangitis is ERCP or MRCP: “string of beads of MRCP or ERCP.” This is the only chronic liver disease in which a liver biopsy is not the most accurate test.

Treatment. Treat with endoscopic therapy for strictures; cholestyramine for itching.


Hemochromatosis

Hemochromatosis is one of the most common inherited genetic diseases. There is an overab- sorption of iron in the duodenum, leading to iron buildup in tissue throughout the body, thus resulting in chronic hepatic inflammation and fibrosis. Presentation include the following:



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A patient presenting with choreoathetoid movements and psychosis gives the clue to perform the slit-lamp examination. Kayser-Fleischer rings are then found, confirming the diagnosis of Wilson disease.


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Treatment. Chronic hepatitis B is treated with interferon, lamivudine, entecavir, telbivudine, or adefovir. Combining these agents does not lead to increased efficacy.

Chronic hepatitis C is now cured with the new combination antiviral drugs. The most commonly used is ledipasvir/sofosbuvir (trade name Harvoni), a 2-drug combination. It is administered as a 1x/ daily pill containing the viral NS5A inhibitor ledipasvir and a nucleotide inhibitor of the viral RNA polymerase, sofosbuvir. Taken daily for 8–12 weeks, it provides cure rates of 94−99% in those infected with genotype 1 (the most common form of hepatitis C in the United States and some European countries), irrespective of the presence or absence of liver cirrhosis or prior unsuccessful treatment. It has also been evaluated for the treatment of infection with other hepatitis C genotypes and has shown promising results in genotypes 3 and 4.


Clinical Recall

Which of the following is not a cause of cirrhosis?

  1. Alpha-1 antitrypsin deficiency

  2. Budd-Chiari syndrome

  3. Hepatitis A

  4. Hemochromatosis

  5. Primary biliary cirrhosis


Answer: C


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Learning Objectives


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ACUTE CHEST PAIN/DISCOMFORT

Chest pain or discomfort is one of the most common complaints that brings patients to the physician’s office or emergency department. Patients presenting with this symptom may have an underlying cause that is benign and requires only moderate analgesic medication, or they may have a life-threatening condition such as acute myocardial ischemia or aortic dissection that mandates prompt diagnosis and treatment. In the evaluation of chest pain, the focus should be on excluding the more serious conditions.


History

Assessing the setting in which the chest pain occurs is one of the most important aspects of the evaluation. The healthy 26-year-old medical resident with chest pain that occurred after on-call is unlikely to have cardiovascular disease, no matter the quality or duration of chest pain. The

  1. year-old man who has type 2 diabetes and dyslipidemia with chest discomfort of any type has a much higher probability for cardiac-related chest pain.

    Overall, the chest pain history is more useful than the physical examination. Important aspects of the history include duration, quality, location, radiation, frequency, alleviating or precipitating factors (especially exercise), and associated symptoms.


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    Inspect the chest wall for tender areas, respiratory motion, respiratory retractions, or accessory muscle use. If the tender area corresponds to the location of the patient’s pain and palpation exactly reproduces the pain, consider musculoskeletal chest pain as the cause of chest pain.

    Abnormal heart sounds and new murmurs are commonly found in certain chest pain syndromes. Wide physiologic splitting of the second heart sound (splitting wider with inspiration) can be found in right bundle branch block or in right ventricular infarction. New paradoxical splitting is most often due to left bundle branch block (LBBB), or anterior or lateral infarction. A new fourth heart sound can occur with angina or infarction. An S3 is more likely due to underlying heart failure. A new murmur may be significant: aortic regurgitation occurs in over half of patients with aortic dissection, while mitral regurgitation can occur in patients with angina or infarction and is due to papillary muscle dysfunction.

    The lungs should be auscultated for crackles and asymmetrical breath sounds. Asymmetry of breath sounds may be found in patients with spontaneous pneumothorax. Absent lung sounds also may occur in pneumothorax and pleural effusions.



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    The extremities should be examined for pulses, edema, calf tenderness, and signs of atherosclerotic vessel disease. Absence of pedal pulses may occur in aortic dissection. Any swelling of the legs, especially if unilateral, raises the odds of pulmonary embolism as the cause of chest pain.


    Testing

    All patients with chest pain should have a 12-lead electrocardiogram (ECG) since the ECG is the single most important test for the evaluation of the cause of chest pain. The ECG should be done immediately after initial stabilization and taking of vital signs.

    Most patients with myocardial infarction will have an abnormal initial ECG:

    In interpreting the ECG, make every effort to obtain previous ECGs, so that abnormalities can be compared with those on the old tracing. Any ECG finding is assumed to be new unless proven otherwise by an old ECG (if one is available). Also, in patients with acute coronary syndromes, the ECG is the sole test required to select patients for emergency reperfusion.

    Serum cardiac biomarker determinations play a vital role in the evaluation of patients who present with acute chest pain and in the diagnosis of acute myocardial infarction. Serum markers such as aspartate transaminase, lactate dehydrogenase, and lactate dehydrogenase subforms no longer are used because they lack cardiac specificity and their delayed elevation precludes early diagnosis. Creatine kinase (CK) is found in striated muscle and tissues of the brain, kidney, lung, and GI tract. This widely available marker has low sensitivity and specificity for cardiac damage. Furthermore, CK levels may be elevated in a number of noncardiac conditions, including trauma, seizures, renal insufficiency, hyperthermia, and hyperthyroidism. Currently, the CK marker largely has been replaced by cardiac troponins and CK-MB.

    CK-MB isoenzyme: CK-MB is cardiac specific and is useful for the early diagnosis of acute myocardial infarction. CK-MB typically is detectable in the serum 4–6 hours after the onset of ischemia, peaks in 12–24 hours, and normalizes in 2–3 days.

    Like the CK level, the peak CK-MB level does not predict infarct size; however, it can be used to detect early reinfarction. Serial CK-MB levels commonly are obtained at admission to the emergency department and are repeated in 6–12 hours.

    CK-MB subforms: CK-MB may be further characterized into subforms (or isoforms).

    CK-MB2 is found in myocardial tissue, and CK-MB1 is found in plasma. The CK-MB subform is not routinely used.

    Cardiac troponins: Troponins (T, I, C) are found in striated and cardiac muscle. Because the cardiac and skeletal muscle isoforms of troponin T and I differ, they are known as the “cardiac troponins.” They are the preferred markers for the diagnosis of myocardial injury. Troponin T and I generally have similar sensitivity and specificity for the detection of myocardial injury.


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    Unlike troponin I levels, troponin T levels may be elevated in patients with renal disease, polymyositis, or dermatomyositis.

    The cardiac troponins typically are measured at emergency department admission and repeated in 6–12 hours. Patients with a normal CK-MB level but elevated troponin levels are considered to have sustained minor myocardial damage, or microinfarction, whereas patients with eleva- tions of both CK-MB and troponins are considered to have had acute myocardial infarction. The cardiac troponins may remain elevated up to 2 weeks after symptom onset, which makes them useful as late markers of recent acute myocardial infarction.

    An elevated troponin T or I level is helpful in identifying patients at increased risk for death or the development of acute myocardial infarction. Increased risk is related to the high serum troponin levels. The troponins also can help identify low-risk patients who may be sent home with close follow-up. Those with a normal or nearly normal ECG and a normal troponin I test 6 hours after admission had a very low risk of major cardiac events (0.3%) during the next 30 days.

    Myoglobin levels begin to rise as early as 1–4 hours after the onset of pain. Normal myoglobin at 4 hours has a very high negative predictive value.


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    Serum enzyme level

    CK-MB Troponin


    Normal


    5 10 15

    Days after infarction


    Figure 5-1. Progression of Cardiac Enzyme Serum Levels


    Chest x-ray should be obtained on patients with chest pain; it may show pneumothorax, pneumomediastinum (i.e., from esophageal rupture), pleural effusion, or infiltrates. Aortic dissection can cause widening of the mediastinum. Subtle findings such as loss of lung volume or unilateral decrease in vascular markings may suggest pulmonary embolism.

    Especially if a noncardiac diagnosis is suspected, arterial blood gases, BNP, and CT angiogram may be helpful for evaluating acute chest pain.


    Causes of Chest Pain

    Aortic Dissection. Pain is sharp, tearing, and extremely severe; typically radiates to back; loss of pulses or aortic insufficiency often develop.


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    Table 5-1. Differential Diagnosis of Conditions Causing Chest Pain

    Noncardiovascular Disorders

    Differentiating Features

    Costochondritis

    Pain exacerbated with inspiration; reproduced with chest wall palpitation

    Hiatal hernia

    Reflux of food; relief with antacids

    GERD

    Acid reflux; relief with antacids

    Peptic ulcer

    Epigastric pain worse 3 h after eating

    Gallbladder disease

    Right upper quadrant abdominal pain and tenderness

    Cardiovascular Disorders

    Differentiating Features

    Myocardial infarction

    Pain more severe, usually >20 min in duration

    Aortic stenosis

    Typical systolic ejection murmur

    Myocarditis

    Pain is usually vague and mild if present

    Pericarditis

    Pain is sharper, pain worse with lying down and relieved by sitting up

    Dissecting aortic aneurysm

    Pain is sharp, tearing, often occurs in back

    Mitral valve prolapse

    Transient pain, midsystolic click murmur, and young female with no risk factors

    Pulmonary Disorders

    Differentiating Features

    Pulmonary embolus-infarction

    Tachypnea, dyspnea, cough, pleuritic pain, hemoptysis

    Pulmonary hypertension

    Signs of right ventricle (RV) failure

    Pneumothorax

    Sudden onset of pain and dyspnea


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    Myocarditis. May be preceded by viral illness; pain is generally vague and mild if present; total CK and MB fraction of CK (CK-MB) are often elevated; conduction abnormalities and Q waves may occur.

    Musculoskeletal Disorders. Most common cause of chest pain. Includes costochondritis, cervical osteoarthritis, radiculitis; pain is atypical, stabbing, localized, may be pleuritic; reproduced by motion or palpation; EKG changes absent.

    GI Disorders. Esophageal reflux is often made worse with recumbency or after meals, may be associated with regurgitation and relieved by antacids; episodes of spasm may be brought on by cold liquids, relieved by nitroglycerin, and may closely resemble angina or infarction; diagnosis may be confirmed by upper endoscopy or esophageal manometry. Peptic ulcer disease, pancreatitis, and cholecystitis may occasionally mimic infarction; abdominal tender- ness is present, with radiation to back and elevated amylase in pancreatitis; sonography can confirm cholecystitis.

    Pneumothorax. Onset abrupt with sharp pleuritic chest pain and dyspnea; breath sounds absent; chest x-ray confirms.

    Pleuritis. Pain is sharp and increases on inspiration; friction rub or dullness may be present; other respiratory symptoms and underlying pulmonary infection usually present.


    Clinical Recall

    Which of the following is the single most important test in the management of chest pain?

    1. CKMB

    2. Troponin

    3. Echocardiography

    4. Electrocardiogram

    5. Chest CT


    Answer: D


    ISCHEMIC HEART DISEASE

    Ischemic heart disease (IHD), also known as coronary heart disease, is an imbalance in coronary oxygen demand and supply resulting from insufficient blood flow. In nearly all cases, the reduction in blood flow is caused by coronary atherosclerotic disease.

    When the atherosclerotic plaque ruptures, there is superimposed thrombus formation that acutely occludes the artery; this is the most common cause of life-threatening acute coronary syndromes.

    Rarely, other abnormalities may occur (coronary artery embolism, coronary artery spasm, coronary arteritis, and coronary artery dissection) which may cause IHD in the absence of atheroma formation.


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    IHD is one of the most prevalent diseases in society, and those affected are likely to die from their disease (though age-specific deaths have declined over the past 30 years). As part of a systemic process that involves all arteries in the body, it is an insidious process that begins in early adulthood with fatty streaks; these lesions progress into plaques and thrombus formation in middle age.


    Ischemic Heart Disease


    Clinically Silent

    (asymptomatic)

    Symptomatic


    Stable angina

    (symptoms with exertion)

    Acute coronary syndromes:


    Intima


    Media


    Atherosclerotic

    plaque

    Ruptured

    plaque


    Progression of

    atherosclerotic plaque Thrombosis formation


    Atherosclerotic

    plaque


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    Figure 5-2. Ischemic Heart Disease


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    The more risk factors a person has, the greater the chance that he will develop heart disease. Also, the greater the level of each risk factor, the greater the risk. For example, a person with total cholesterol 260 mg/dL has a greater risk than someone with total cholesterol 220 mg/dL, even though all people with total cholesterol ≥220 mg/dL are considered high risk.


    Major Modifiable Risk Factors

    Elevated cholesterol levels: The risk of IHD rises as blood cholesterol levels increase. The con- centrations of lipid fractions, especially low-density lipoprotein (LDL) and high-density lipoprotein (HDL), are also important. LDL cholesterol is the single most important subgroup that carries risk for IHD, although there are several other abnormalities

    that increase coronary risk: low HDL cholesterol, hypertriglyceridemia, increased

    total-to-HDL-cholesterol ratio and increased lipoprotein A. When other risk factors (such as high blood pressure and tobacco smoke) are present, this risk increases even more.


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    Proof of the importance of serum cholesterol has come from randomized trials, which showed that reductions in total LDL levels reduce coronary events and mortality.

    Tobacco: Cigarette smoking is an important factor for IHD because a smoker’s risk of heart attack is >2x that of a nonsmoker. Cigarette smoking also acts with other risk factors (hypertension, dyslipidemia) to greatly increase the risk for IHD.

    Hypertension (HTN): HTN is a well-established risk factor for increase in risk of myocardial ischemia, stroke, kidney failure, and heart failure. Studies in the general population have shown that the risk for cardiovascular events increases at BP >110/75 mm Hg. Systolic BP is as important as diastolic BP in terms of risk for IHD, especially in older patients.

    Treatment of HTN to optimal levels reduces the risk of IHD and all cardiovascular events. In fact, data from recent randomized trials suggest that reducing BP below previously recommended levels is beneficial in high-risk patients.

    Physical inactivity and exercise: Inactivity and sedentary lifestyle are risk factors for IHD. Exercise of moderate degree has a protective effect against IHD and cardiovascular events. More vigorous activities are associated with more benefits. Physical activity can help increase HDL cholesterol and control diabetes and obesity, as well as help to lower blood pressure.

    Obesity: Patients with increased body fat (elevated body mass index), especially if a lot is in the waist area, are more likely to develop heart IHD and stroke. Excess weight raises blood pressure, blood cholesterol, and triglyceride levels, and it lowers HDL cholesterol levels. It can also increase risk for type 2 diabetes by causing insulin resistance.

    Studies have shown that loss of as little as 10–20 lb can significantly reduce the risk of cardiovascular disease.

    Diabetes mellitus: Elevated blood glucose levels and insulin resistance are associated with IHD and overall cardiovascular events. All-cause mortality in diabetic patients is

    comparable to that of all-cause mortality in patients with prior myocardial ischemia; hence, diabetes is now considered an “IHD equivalent.” Even when glucose levels are under control, diabetes greatly increases the risk of IHD. Almost 75% of patients with diabetes die of some form of cardiovascular disease.

    There is compelling evidence that aggressive treatment of HTN and cholesterol, as well as tight glycemic control, reduces the risk of cardiovascular events in these patients significantly.


    Major Unmodifiable Risk Factors

    Age: Four out of 5 people who die of IHD are age ≥65. Also, women who develop myocardial ischemia at older ages have a higher mortality than men within the first few weeks of the cardiac event.


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    Sex: Men have a greater risk of IHD than women, and overall they develop cardiovascular disease earlier in life.

    Heredity: Family history is a significant independent risk factor if there is a family history of premature disease (age <55 in male relative and <65 in female relative).


    Minor Contributing Factors

    Sex hormones: Men have more heart attacks than women before menopause. Several studies show that the decrease of natural estrogen as women age may contribute to a higher risk of heart disease after menopause.

    Stress: Various studies have shown relationship between IHD risk and stress in a person’s life. This may be a true association or just a secondary correlation: for example, people under stress may overeat, start smoking, or be less active than people who are not under stress.


    Myocardial Ischemia As a Manifestation of IHD

    During ischemia, an imbalance occurs between myocardial oxygen supply and demand. Ischemia may manifest in any of the following ways:

    Myocardial ischemia can be caused by increased myocardial oxygen demand, reduced myocar- dial oxygen supply, or both. In the presence of coronary obstruction, an increase of myocardial oxygen requirements caused by exercise, tachycardia, or emotion leads to a transitory imbal- ance. (This condition is called “demand ischemia” and is responsible for most episodes of chronic stable angina.)

    In other situations, the imbalance is caused by acute reduction of oxygen supply secondary to marked reduction or cessation of coronary flow as a result of platelet aggregates or thrombi. This condition (“supply ischemia”) is responsible for myocardial infarction (MI) and most episodes of unstable angina (UA). In many circumstances, ischemia results from both an increase in oxygen demand and a reduction in supply.


    Angina (Stable Angina)

    A 62-year-old man presents with substernal chest pain that occurs with exertion and is relieved by rest. He has been having this on and off for 8 months, and the last episode occurred 3 days ago while he was running to the bus. He has a history of well-controlled diabetes and dyslipidemia. Vital signs, physical examination, and ECG are normal. An exercise stress test shows a 2-mm ST depression.


    Stable angina occurs when the myocardium becomes ischemic. This occurs during periods of increased demand for oxygen, such as exercise, or decreased supply, such as hypotension or


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    anemia (see demand ischemia, above). Stable angina is typically a substernal pressure lasting 5–15 minutes. It may be accompanied by radiation to the jaw, neck, shoulders, or arms. It is less likely to have the symptoms often associated with MI: sweats, nausea, and shortness of breath. Anginal pain is not typically affected by respiration or by position. Typically, patients with stable angina will have pain after a predictable amount of exertion and will have identical symptoms with each attack.

    In certain patients, symptoms other than pain may occur. For example, a profound sense of weakness and breathlessness may be an “angina equivalent.” Atypical symptoms are more likely to occur in the elderly and in diabetics.

    The physical exam is usually normal. A new S4 may be heard, suggesting a stiff ventricle due to ischemia.

    Most patients with angina will have ECG changes during an attack. Most commonly, ST segment depression is seen. ST segment elevation occurs in variant angina (Prinzmetal angina) where coronary artery spasm is responsible and rarely during ischemia caused by stable angina (where atherosclerotic disease is responsible).

    Diagnosis. The exercise treadmill test (exercise stress test) is the most useful test for evalu- ating the cause of chronic chest pain when there is concern about IHD (stable angina).

    Exercise stress testing provides a controlled environment for observing the effects of increases in the myocardial demand for oxygen. In order to do an appropriate analysis, a target heart rate must be reached.


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Other: A beta blocker should be given unless contraindicated. IV nitroglycerin (NTG) can be given for refractory pain.

In patients with diabetes, good glycemic control should be targeted in the hospital and after discharge. This may require considering an insulin-based regimen in hospital.


Invasive management

Early coronary angiography (within 48 hours) and revascularization are recommended in patients with NSTEMI and high-risk features, except in patients with severe comorbidities. Pain or ischemia refractory to medical therapy and high-risk features on early exercise testing can also identify patients suitable for early invasive therapy.


Clinical Recall

Which of the following medications must be withheld before performing an exercise stress test?

  1. Clopidogrel

  2. Metoprolol

  3. Nimodipine

  4. Aspirin

  5. Lisinopril


Answer: B


ST Elevation MI

The pain of typical MI (STEMI; in the past referred to as Q wave MI) is substernal, diffuse with a pressure quality. It may radiate to the neck or jaw, shoulders, or arms. Often, the pain is accompanied by additional symptoms, such as dizziness (lightheadedness), nausea or vomiting, diaphoresis, or shortness of breath (dyspnea).

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The symptoms of MI last >20 minutes and do not respond completely to nitroglycerin. The duration of the pain is variable. Pain may resolve completely after a few hours or may persist for over a day.

Elderly or diabetic patients are prone to atypical symptoms such as nausea or dyspnea as the sole symptoms of infarction. As many as 20% of MI are “silent”—that is, whatever symptoms were present did not impress the patient enough for them to seek medical care or even to remember the incident.

The exam usually shows the patient to have anxiety and pain.

Diaphoresis is often present.

Pulse rate may be normal, but often bradycardia is present in inferior infarctions. Tachycardia is often seen with large infarctions.

Blood pressure is often elevated.

Cardiac exam is usually normal.

Large infarctions may cause signs of ventricular failure or valve dysfunction. A fourth heart sound (S4) is common due to a stiffened ventricle. Mitral regurgitation may occur if papillary muscles malfunction. The second heart sound may be paradoxically split as the left ventricular contraction time increases due to LBBB and weakened left ventricle.

Later in the course of MI, other findings may be present: mild fever, pericardial friction rub, ventral septal defect murmur due to septal rupture, or severe mitral regurgitation due to papillary muscle rupture.

STEMI is defined as clinical symptoms consistent with ACS and ECG features including any of these:

Persistent ST-segment elevation of ≥1 mm in 2 contiguous limb leads

ST-segment elevation of ≥2 mm in 2 contiguous chest leads

New LBBB pattern

Initially, you don’t need increased cardiac biomarkers (troponin, CPK-MB, etc.) to make the diagnosis of STEMI (although these are usually eventually positive at some point during the course of the disease).

Initial nonspecific management for all patients with possible MI (anyone with a compatible chest pain history) is to keep them on a cardiac monitor. Oxygen therapy and an IV line should be established as quickly as possible. Aspirin should be given unless contraindicated, as early as possible. Nitroglycerin and pain control (morphine) should be given as required.

Patients with STEMI usually have a completely occluded coronary artery with thrombus at the site of a ruptured plaque. This eventually leads to myonecrosis. Restoring coronary patency (emergency reperfusion) as promptly as possible is a key determinant of short-term and

long-term outcomes.

Patients with STEMI who present within 12 hours of the onset of ischemic symptoms should have a reperfusion strategy implemented promptly. Reperfusion may be obtained with fibrinolytic therapy or percutaneous coronary intervention (PCI).

Patients presenting with NSTEMI will not benefit from thrombolytics.


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I







a

V

R





V

1







V4






































II







a

VL






V

2







V5






































II

I






a

V

F





V

2







V6








II




























































V

I



























































V

5






























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Figure 5-4. Anteroseptal STEMI with Changes in V1–V3



I

a

V

R

V

1

V4



II


a


VL


V


2


V5



III

V

V

3

V6


VI


image

V

F

a

Figure 5-5. Inferior STEMI with Changes in II, III, and aVF


I

a

V

R

V

1

V4


II

a

VL

2

V5


III

a

VF

2

V6



V1

II

V

V5


Figure 5-6. NSTEMI Affecting Leads II, III, and aVF

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Table 5-2. Localization of STEMI


Area of Infarction

EKG Changes (Q Waves, ST Elevation, T Wave Inversions)


Artery Involved

Inferior

II, III, aVF

Right coronary

Anteroseptal

V1–V3

Left anterior descending

Anterior

V2–V4

Left anterior descending

Lateral

I, aVL, V4, V5, and V6

Left anterior descending or circumflex

Posterior

V1–V2: tall broad initial R wave, ST depression, tall upright T wave; usually occurs in association with inferior or lateral MI

Posterior descending

Table 5-3. Typical Electrocardiographic Evolution of a STEMI

EKG Abnormality

Onset

Disappearance

Hyperacute T waves (tall, peaked T waves in leads facing infarction)

Immediately

6–24 hours

ST-segment elevation

Immediately

1–6 weeks

Q waves longer than 0.04 seconds

One to several days

Years to never

T wave inversion

6–24 hours

Months to years


Emergent reperfusion therapy

The choice of reperfusion therapy is between PCI and thrombolysis therapy. PCI is the best available treatment if provided promptly. PCI improves short-term and long-term outcomes (reduction of deaths and MI) in patients with STEMI presenting within 12 hours when compared with thrombolytic therapy. This benefit over thrombolysis may occur only if the additional time delay associated with PCI is <1 hour. In general, a time delay of 90 minutes from first medical encounter to PCI is the maximum desirable. For patients presenting with STEMI at a facility without PCI access, transfer to another facility capable of performing PCI usually takes too long. Where PCI is delayed or not available, reperfusion with thrombolytic therapy should occur unless contraindicated.

Thrombolytics (Fibrinolytics)

Thrombolytics such as streptokinase or tissue-type plasminogen activator (tPA) restore perfu- sion to the ischemic area by lysing the clot, thereby reducing infarct size and improving survival.

Thrombolysis benefits patients with all types of ST elevation infarction, but the benefit is several times greater in those with anterior infarction. The earlier the treatment is given, the greater the absolute benefit. The greatest benefit is in patients with ST elevation or new left bundle branch block who have had symptoms for <12 hours.


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Streptokinase and alteplase are given by IV infusion. Reteplase and tenecteplase can be given by rapid bolus injection. tPA is the most common agent used in the U.S. Prolonged persis- tence of antibodies to streptokinase may reduce the effectiveness of subsequent treatment; therefore, streptokinase should not be used if used within the previous 12 months in the same patient. Complexity of administration differs among the different thrombolytics: tenecteplase and reteplase are ready in about 1 minute; for streptokinase or tPA, the typical time from physician order to administration is 12 to 15 minutes.

Bottom line: consider a thrombolytic agent as an alternative to primary PCI in suitable candi- dates with:

Late presentation (>12 hours after symptom onset): Reperfusion therapy with either PCI or fibrinolysis is not routinely recommended in patients who are asymptomatic and hemodynam- ically stable, and who present >12 hours after symptom onset.

Other interventions may include coronary artery bypass grafting (CABG). CABG surgery may occasionally be more appropriate—particularly in patients who have suitable anatomy and are not candidates for fibrinolysis or PCI. CABG surgery may also be considered in patients with cardiogenic shock or in association with mechanical repair.


Adjuvant therapy used together with reperfusion

Antiplatelet Therapy

Aspirin should be given to all patients with presumed STEMI unless contraindicated, and, in the absence of significant side effects, low-dose therapy should be continued in the long term.

Clopidogrel or prasugrel should be prescribed in addition to aspirin for patients undergoing PCI with a stent. Ticagrelor is an alternative to clopidogrel or prasugrel.


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In patients selected for fibrinolytic therapy, clopidogrel should be given in addition to aspirin, unless contraindicated. Note, however, that if it is thought that the patient is likely to require CABG acutely, clopidogrel should be withheld.

Clopidogrel should be continued for at least a month after fibrinolytic therapy, or for up to 9–12 months after stent implantation, depending on the type of stent used.

Antithrombin Therapy

With PCI: Antithrombin therapy should be used in conjunction with PCI. The dose of unfractionated heparin therapy will depend on concomitant use of glycoprotein (GP) IIb/IIIa inhibitors. It may be advisable to give a bolus of heparin while the patient is in transit to the catheterization laboratory.

The role of enoxaparin in acute STEMI in conjunction with PCI remains to be fully determined, but it appears to be safe and effective.

With fibrinolysis: Antithrombin therapy should be used with fibrin-specific fibrinolytic agents.

IV unfractionated heparin should be given as an initial bolus, adjusted to attain the activated partial thromboplastin time (APTT) at 1.5 to 2 times control. IV unfractionated heparin is used when rapid reversal is needed. The half-life is shorter with unfractionated heparin.

Glycoprotein IIb/IIIa Inhibitors

It is reasonable to use abciximab with primary PCI. Eptifibatide and tirofiban are the other GPIIb/IIIa inhibitors. Full-dose GP IIb/IIIa inhibitors should be avoided with fibrinolytic therapy as there is evidence of excessive bleeding (including intracranial hemorrhage) with this combination.

The combination of GP IIb/IIIa inhibitors with reduced doses of fibrinolytic therapy is not recommended. There is no significant advantage over full-dose fibrinolytic therapy alone, and the risk of bleeding is increased, particularly in the elderly.


Cardiac surgery

Emergency bypass surgery should be considered in patients with STEMI and: (1) failed PCI with persistent pain or hemodynamic instability and coronary anatomy suitable for surgery or (2) persistent or recurrent ischemia refractory to medical therapy and suitable anatomy.


Recommended discharge medications after ACS

  1. Aspirin: All patients should take daily unless contraindicated.

  2. Clopidogrel: There is evidence that clopidogrel or prasugrel should be prescribed for up to 9–12 months after acute myocardial infarction, particularly after stent placement. Clopidogrel may also be prescribed as an alternative when aspirin is contraindicated, or to those intolerant to aspirin, in patients with recurrent cardiac events.

  1. Beta-blocker: These drugs should be prescribed for all patients after an ACS unless contraindicated, and continued indefinitely. Metoprolol and carvedilol particularly should be used in patients after ACS who have heart failure.


    Note

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    To remember issues that need to be considered at the time of discharge, remember “ABCDE” (aspirin and anti- anginals, beta blockers and blood pressure, cholesterol and cigarettes, diet and diabetes, education and exercise).


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    1. ACE inhibitors: Should be given in patients with ACS in CHF, left ventricular dysfunction (ejection fraction <40%). Its use should be reviewed later on the course of the patient and discontinued if the heart failure resolves.

    2. Statins: Statin therapy should be initiated in the hospital in all patients with ACS (the exception is the rare ACS that is not related to atherosclerosis).

    3. Nitrates: Long-acting nitrates (isosorbide) should be reserved for the patients with persistent chest pain.

    4. Warfarin: It is recommended after ACS only for those at high risk of systemic throm- boembolism because of atrial fibrillation or mural thrombus.

    Secondary prevention through the control or elimination of known risk factors for coronary artery disease (e.g., hyperglycemia in patients with diabetes mellitus, HTN control, tobacco cessation, physical inactivity) also should be part of discharge planning.


    You are asked by your patient, who has a history of ischemic heart disease, about drug treatments that have been shown to decrease mortality in his case. (It doesn’t matter if he has stable angina or prior history of acute coronary syndrome.)


    Answer: Lipid lowering agents (statins), ASA, Beta-blocking agents and CABG in patients with triple vessel disease or left main disease.


    Other testing in ACS

    Exercise ECG testing: Increasingly, submaximal testing is performed 4–7 days after infarction. A maximal test can be performed at 3–6 weeks postinfarction. It is used to assess prognosis and to identify those patients with reversible ischemia who should then have an angiogram (if one has not been done) to assess the need for coronary artery bypass graft.

    Myocardial perfusion imaging can be performed before hospital discharge to assess the extent of residual ischemia if the patient has not already undergone cardiac catheterization and angiography.


    Complications of ACS

    Electrical disturbances dysrhythmias


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Pump dysfunction

Contractile dysfunction: left ventricular, right ventricular, and biventricular failure; true ventricular aneurysm; infarct expansion

Mechanical disruption: acute mitral regurgitation (papillary muscle dysfunction or rupture), ventricular septal rupture, free wall rupture, pseudoaneurysm; treated with emergency surgical repair

Electromechanical dissociation


Ischemia

Postinfarction ischemia: ischemia in the infarct and ischemia distant to the infarct

Early recurrent infarction or infarct extension

Postinfarction angina after thrombolytics or PCI should be treated with bypass surgery


Pericarditis—Dressler syndrome (late)

Treated with aspirin, NSAIDs, and later steroids if there is no response.


Thromboembolic

Mural thrombus with systemic embolism

Deep vein thrombosis with prolonged immobilization


Sudden cardiac death

Most often due to arrhythmia.

Ventricular fibrillation (most commonly)

Ventricular tachycardia


Right ventricular infarction

Accompanies 30% of inferior MIs. It is diagnosed with RV leads and treated with fluids.


Non-Cardiac Complications of ACS

Depression is 3x more common in those who have had a heart attack than in the general population, with 20% of heart attack victims qualifying for a diagnosis of major depressive disorder, and a far greater proportion experiencing increased levels of depressive symptoms. Beyond the accompanying emotional distress and suffering, depression also increases one’s risk of having another heart attack or dying over the ensuing months and years.

There is reliable evidence that both antidepressant medications and certain forms of psycho- therapy are effective in reducing depression in the post-MI state. Selective serotonin reuptake inhibitors (SSRIs) such as sertraline and citalopram have been found to be both effective in reducing depression and relatively safe for use in patients with coronary heart disease. Cognitive behavior therapy has also been found to be effective in treating depression.



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Erectile dysfunction (ED) is prevalent among patients with CAD and post-MI (in some series ~ 40%).

High-risk: those with unstable angina, MI within 2 weeks, poorly controlled hypertension, severe CHF (New York Heart Association class III/IV), significant arrhythmias, severe cardiomyopathies; patients should be referred for cardiovascular evaluation and stabilization prior to recommending resumption of sexual activity.


Nonatherosclerotic Acute Coronary Syndromes

Although thrombotic complications of the atherosclerotic process account for most cases of acute coronary syndromes, there are a few rare etiologic factors that have been proposed as causes of or contributors to acute coronary occlusion. These causes include coronary artery spasm, spontaneous coronary dissection, coronary artery embolization, coronary arteritis, and hypercoagulability states such as factor V gene mutation, deficiencies of proteins C and S, antithrombin III deficiency, antiphospholipid antibody syndrome, and prothrombin gene


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mutation. Cocaine use has been documented to induce coronary vasoconstriction in nondis- eased coronary segments but is more pronounced in atherosclerotic segments.

Prinzmetal angina, or variant angina, is a very uncommon condition in which episodes of severe angina are triggered when one of the major coronary arteries suddenly goes into spasm. These episodes are accompanied by ST-segment elevation on the ECG. Although the spasm almost always terminates spontaneously, Prinzmetal angina may be associated with acute MI, serious ventricular arrhythmias, and sudden death.

As opposed to typical angina, Prinzmetal angina usually occurs during periods of rest, most often at night and in the early morning hours. Frequently, episodes appear in clusters. In men, Prinzmetal angina is often associated with atherosclerosis; in women it is not. Women with Prinzmetal tend to have few risk factors for CAD, though many have a history of migraine headaches (another condition associated with arterial spasm).

Exercise testing and routine coronary angiography usually give normal results. Ergonovine has been used to trigger coronary artery spasm in susceptible patients, confirming the diagnosis. Treatment with calcium channel blockers or nitrates eliminates spasm in most of these patients. Once adequately treated, their prognosis is good.

During an acute episode of pain and ST segment elevation, you cannot tell who has Prinzmetal variant angina and who has an acute ST elevation MI. Therefore, you must initially treat everyone with chest pain and ST elevation as if they were having an acute MI. Prinzmetal angina can be confirmed only after coronary angiography.


Causes of MI without Coronary Atherosclerosis


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Clinical Recall

Which of the following is not an absolute contraindication to thrombolytic therapy?

  1. Active bleeding from factor VIII deficiency

  2. Epidural hematoma within the last 3 months

  3. Cholecystectomy 3 weeks ago

  4. Prior basal ganglia hemorrhage

  5. Large MCA stroke within the last 3 months


Answer: C


CONGESTIVE HEART FAILURE (CHF)

Heart failure (HF) arises from the inability of the ventricle to efficiently pump blood through- out the circulation. Clinically HF presents with symptoms of breathlessness, exercise intoler- ance, and fatigue.


Case 1:

A 62-year-old man with hypertension and dyslipidemia presents with dyspnea and lower-extremity edema for 2 months. On exam there is jugular venous distention (about 9 cm.), an S3 gallop, and the apical impulse is displaced to the left of the mid-clavicular line at the 6th intercostal space. The chest x-ray shows enlarged cardiac silhouette. The echocardiogram shows a dilated left ventricle with an ejection fraction of 35%.


Case 2:

A 57-year-old man with history of multiple myeloma presents with dyspnea and lower-extremity edema for 2 months. On exam there is jugular venous distention (about 8 cm.), an audible S4, and the apical impulse is non-displaced at the 5th intercostal space. The chest x-ray shows normal cardiac silhouette. The echocardiogram shows a thickened left ventricle with an ejection fraction of 65%.


As HF evolves, changes in vascular function, blood volume, and neurohumoral status occur throughout the body. These changes serve as compensatory mechanisms to help maintain car- diac output (primarily by the Frank-Starling mechanism) and arterial blood pressure (by sys- temic vasoconstriction). However, these compensatory changes over time can worsen cardiac function. Cardiac changes during HF include increased end-diastolic volume; ventricular dila- tation or hypertrophy; decreased stroke volume and cardiac output; reduced ejection fraction


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(systolic dysfunction) or impaired filling (diastolic dysfunction). Compensatory mechanisms during HF include:

Cardiac: Frank-Starling mechanism, tachycardia, ventricular dilatation

Neuronal: increased sympathetic adrenergic activity, reduced cardiac vagal activity

Hormonal: activation of angiotensin-aldosterone system, vasopressin, catecholamines, and natriuretic peptides

In clinical practice, HF is commonly categorized by whether the abnormality is due to contrac- tion or relaxation of the heart. Systolic HF (systolic dysfunction) is due to a loss of contractile strength of the myocardium accompanied by ventricular dilatation. This type of HF is also accompanied by a decrease in normal ventricular emptying (usually ejection fraction <45%). Examples of systolic HF include ischemic cardiomyopathy and dilated cardiomyopathy (Case 1 in this section).

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Heart failure with preserved ejection fraction (diastolic dysfunction) occurs when the filling of one or both ventricles is impaired while the emptying capacity is normal (echocardiogram confirms that the ejection fraction is normal). The infiltrative cardiomyopathies (amyloidosis) are typical examples (Case 2 in this section).


Impaired



LV function



i LV filling pressure

Peripheral edema




i systemic vascular resistance


image

Reflex arteriolar vasoconstriction

cardiac output

stroke volume

i afterload

(LV impedance)

renal perfusion

i blood volume


NaCl and H20 retention


i renin

i angiotensin II i aldosterone i vasopressin


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Figure 5-7. Inter-related Cycles in Congestive Heart Failure


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Congestive HF indicates a clinical syndrome of dyspnea and fatigue as well as evidence of features of circulatory congestion (peripheral edema, elevated jugular venous pressure [JVP]). In heart failure, intravascular congestion occurs with elevation of left ventricular diastolic and pulmonary venous pressures that eventually causes transudation of fluid from the pulmonary capillaries into the interstitial space. Pulmonary edema develops when the rate of fluid accumulation goes above the rate of lymphatic absorption. Pulmonary edema is detected by audible crackles, increased JVP and edema on exam, and chest x-ray findings.


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Clinical Pearl

In the work-up of patients with new-onset HF, always try to identify potentially reversible causes.

Wikipedia, James Heilman, MD


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Figure 5-8. Elevated JVP


Decompensated HF or exacerbation of HF denotes worsening of symptoms and clinical findings in pre-existing HF. This can be due to precipitating factors such as non-adherence to medication, increase in dietary salt, acute ischemia, tachycardia, or pulmonary infection.

In evaluating patients with HF or worsening of pre-existing HF, it is also important to exclude precipitating factors. Commonly, HF manifests for the first time when a precipitating factor places additional burden on the heart. Such factors include:

HF may occur as a consequence of most causes of heart disease, but ischemic heart disease is responsible for over 70% of all cases in the western world. Other common causes include: hypertensive heart disease, the cardiomyopathies (idiopathic, alcohol related, etc.), and valvular and congenital heart diseases.

Symptoms of HF include dyspnea (differentiate from pulmonary dyspnea), orthopnea, paroxysmal nocturnal dyspnea, and fatigue/weakness.


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Physical findings in HF:

Pulmonary rales

Table 5-4. Most Common Causes of Acute Pulmonary Edema

Ischemia

Arrhythmia

Non-adherence with medication

Dietary indiscretion

Infection


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Clinical Pearl

In the work-up of patients with exacerbation of HF, always:

Check cardiac enzymes to exclude myocardial ischemia or infarction

Do a chest x-ray to exclude infection

Peripheral edema, ascites

Hepatomegaly

Jugular venous distention

Displaced apical impulse (systolic HF)


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Wikipedia, James Heilman, MD


Figure 5-9. Pitting Edema


The severity of heart failure is commonly classified by using a HF staging system. The New York Heart Association Functional Classification (NYHA staging system) relates symptoms to everyday activities and the patient’s quality of life:

Class I: patients have no limitation of activity; they suffer no symptoms from ordinary activities

Class II: patients with slight, mild limitation of activity; they are comfortable with rest or with mild exertion


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Clinical Pearl

The single best test for the evaluation and diagnosis of heart failure is the echocardiogram.


Note

BNP is used acutely if the cause of dyspnea is not clear.


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Copyright 2007 Gold Standard Multimedia Inc.


Figure 5-10. Chest X-ray Demonstrating Acute Exacerbation of Congestive Heart Failure


Diagnosis. Echocardiography is the test-of-choice to confirm the diagnosis of HF and to classify the type (systolic vs. diastolic). With the echocardiogram, the clinician is able to determine ejection fraction and identify valvular heart disease as well as other cardiac anoma- lies (dilated ventricle, thickened ventricle, etc.).

Chest x-rays are also used to aid in the diagnosis of heart failure. They may show cardiomegaly, vascular redistribution, Kerley B-lines, and interstitial edema.

Electrocardiogram is used to identify ventricular hypertrophy and/or the presence of isch- emic heart disease, arrhythmias, or conduction delays which may cause or precipitate HF.

Brain Natriuretic Peptide (BNP) is a polypeptide secreted by the heart in response to excessive stretching of the myocytes. It is a valuable tool in the evaluation of patients with presumed HF or decompensated HF in the acute setting. The BNP is almost always elevated (97% sensitivity) in patients with decompensated HF. Normal BNP excludes CHF as the cause of dyspnea.

Management. The treatment goals in HF are to improve hemodynamics, relieve symptoms (improve quality of life), and prolong survival. Remember, always evaluate for reversible causes at the same time.

Non-pharmacologic treatment includes primarily reduction of salt intake.

For pharmacologic treatment, ACE inhibitors are the basis of therapy and recommended for all patients with HF (especially systolic HF), irrespective of blood pressure status. They improve survival and reduce ventricular hypertrophy—and eventually, symptoms. ACE inhibitors through vasodilation reduce preload and afterload, thereby reducing right atrial, pulmonary



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arterial, and pulmonary capillary wedge pressures. All ACE inhibitors have been studied and are considered equal in terms of HF treatment. Angiotensin receptor blockers (ARB) are acceptable alternatives if the patient is unable to tolerate ACE inhibitors (cough, angioedema).

Diuretic therapy, especially loop diuretics, is the treatment of choice for the relief of acute pulmonary edema symptoms. Several classes are used but the loop diuretics (furosemide) class is the most commonly used. Thiazide diuretics (hydrochlorothiazide) are useful only in mild HF. Spironolactone and eplerenone (aldosterone antagonists) have been used as add-on therapy to ACE inhibitors in severe heart failure to prolong survival by presumed aldosterone inhibition.


Table 5-5. Vasodilators Used in Congestive Heart Failure


Drug


Site of Action

Route of Administration


Complications

Captopril Enalapril Lisinopril

Arteriolar and venous ACE inhibitor

Oral

Rash, nonproductive cough, proteinuria, renal failure, taste disturbance, agranulo- cytosis, hypotension

Nitroprusside

Arteriolar and venous

IV

Thiocyanate toxicity, methemoglobinemia

Nitroglycerin

Venous (arteriolar at high doses IV)

SL, IV, cutaneous ointment, or patch

Headache, postural hypotension, methemoglobinemia

Isosorbide dinitrate

Venous

Oral or SL

Headache, postural hypotension

Hydralazine

Arteriolar

Oral

Positive ANA, SLE-like syndrome (10–20% if >400 mg/d) drug fever, rash


Chronic adrenergic activation has been implicated in the pathogenesis of HF and thus β-adrenergic blocking agents are an important part of HF therapy. Along with ACE

inhibitors, beta blockers have been demonstrated to decrease mortality, reduce hospitaliza- tions, improve functional class, and improve ejection fraction in several large-scale, randomized, placebo-controlled trials.

Start patients on beta blockers after stabilization of symptoms with diuretic and ACE inhibitor therapy, irrespective of blood pressure status. Beta blockers such as carvedilol, metoprolol, and bisoprolol have demonstrated survival benefits in trials.


Note

ACE inhibitor (any) and a diuretic are considered first line for all patients with HF. Once the patient is stable, add carvedilol or metoprolol. Don’t

substitute β-blockers in HF since not all β-blockers have the same efficacy.


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Note

Agents which lower mortality in systolic dysfunction


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Remember that K+ and digitalis compete for myocardium binding sites. Hyperkalemia will decrease digitalis activity, whereas hypokalemia results in toxicity.

Digitalis will increase both the force and the velocity of the myocardial contraction. It will also promote a more complete emptying of the ventricles.

It is used for the treatment of:

CHF

Atrial fibrillation/flutter

Paroxysmal atrial tachycardia/SVT

Conditions which predispose to digitalis toxicity are:

Renal insufficiency

Electrolyte disturbances (hypokalemia, hypercalcemia, hypomagnesemia)

Advanced age

Sinoatrial and atrioventricular block

Thyroid disease, especially hypothyroidism


Table 5-7. Drug Interactions Associated with Digoxin

Drug

Effect*

Mechanism

Quinidine

Increase

Decreases renal clearance of digoxin

Verapamil, diltiazem

Increase

Decreases renal clearance of digoxin

Cholestyramine, colestipol

Decrease

Binds digoxin in GI tract; interferes with enterohepatic circulation

Spironolactone

Increase

Inhibits tubular secretion of digoxin

Thiazides, furosemide

Increase

Diuretic-induced hypokalemia and/or bumetanide hypomagnesemia potentiates digitalis action

*Increase enhances digitalis effect; decrease diminishes digitalis effect.


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Agents which improve heart failure symptoms but do not reduce mortality

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Clinical Pearl

Diastolic HF may worsen when diuretics and vasodilators are used excessively. The goal in diastolic HF is to slow the heart rate with beta blockers and calcium channel blockers (verapamil, diltiazem) in order to allow adequate diastolic filling.

Sympathomimetic amines (dopamine, dobutamine) and phosphodiesterase inhibitors (amri- none, milrinone) are sometimes used in the management of severe acute HF (hospitalized patients). They must be administered by IV infusion and need continuous monitoring of the blood pressure and cardiac rhythm.

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Monitoring of patients with HF includes calculation of fluid intake and excretion (in the hospi- tal) as well as monitoring body weight (in the out-patient setting).

In refractory HF (defined as progression of HF despite standard treatment), the patient may be considered for: biventricular pacing, implantable defibrillator, and heart transplantation.


Medical Devices for Systolic Dysfunction

The automatic implantable cardioverter/defibrillator (AICD) is a standard therapy for ischemic dilated cardiomyopathy. Since the most common cause of death in CHF is an arrhythmia, it is logical that a device which interrupts arrhythmia will lower mortality. A biventricular pace- maker will “resynchronize” the heart when there is dilated cardiomyopathy and QRS >120 mSec. When there is a wide QRS, the 2 ventricles do not beat or depolarize in synchrony.

When you put a biventricular pacemaker into the heart, this will “resynchronize” the 2 ventricles, resulting in an immediate decrease in symptoms.

When do I answer AICD?

ACE inhibitors are a class effect; there is no difference in efficacy between the drugs. There is no benefit to adding an ARB to an ACE inhibitor. With beta blockers, not all the drugs are equal; those that benefit mortality in CHF are metoprolol, carvedilol, and bisoprolol. Biven- tricular pacemakers and cardiac resynchronization therapy also have implantable defibrillator function.


Pulmonary Edema

Pulmonary edema is considered a medical emergency and requires hospitalization. It leads to impaired gas exchange and may cause respiratory failure. There are non-cardiogenic causes of pulmonary edema but in this section we will discuss only cardiogenic pulmonary edema.

Cardiogenic pulmonary edema is caused by an acute increase in left ventricular pressure due to ventricular dysfunction which leads to fluid accumulation in the pulmonary interstitium.


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Signs and Symptoms

Increased respiratory rate

Cough with expectoration (pink frothy sputum)

Cyanosis

Nocturnal dyspnea

Rales, rhonchi, wheezing

Chest X-ray Findings

Prominent pulmonary vessels

Effusions

Enlarged cardiac silhouette

Kerley B lines

EKG is used to determine if an arrhythmia is contributing to the development of the pulmonary edema.

Treatment

Oxygen

Diuretic therapy (furosemide) reduces preload

Morphine sulfate; side effects include respiratory depression and rarely hypotension

Sitting the patient upright

Nitroglycerin to reduce preload

Digoxin if in atrial fibrillation

IV ACE inhibitors


Clinical Recall

What is the most appropriate therapy for the treatment of hypertrophic cardiomyopathy?

  1. Diltiazem

  2. Nifedipine

  3. Lisinopril

  4. Digoxin

  5. Spironolactone


Answer: A


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VALVULAR HEART DISEASE


Mitral Stenosis

Mitral stenosis is the most common lesion caused by rheumatic fever, with possible progression to right ventricular failure. It becomes clinically symptomatic during pregnancy. Mitral stenosis consists of thickened mitral valve leaflets, fused commissures, and chordae tendineae.

Most cases are secondary to rheumatic fever. Rarely, it is caused by a congenital defect, calcification of the valve, or post-radiation treatment to the chest.

Pathogenesis. Mitral valve stenosis impedes left ventricular filling. Increased left atrial pressure is referred to the lungs, causing pulmonary congestion. Forward cardiac output becomes reduced, secondary pulmonary vasoconstriction occurs, and eventually right ventricular failure results.

Clinical Symptoms. Usually manifest slowly over years.


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Diagnosis is made with the following:

EKG


Mitral Regurgitation

Mitral regurgitation is backflow of blood from the left ventricle into the left atrium, due to inadequate functioning (insufficiency) of the mitral valve (most commonly from ischemia). Men are more affected than women.

The etiology of mitral regurgitation is due to abnormalities of the mitral leaflets, annulus, and chordae tendineae. Common causes include hypertension, CHF, ischemic heart disease, rheumatic fever, and any cause of dilation of the left ventricle.


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Table 5-8. Acute versus Chronic Etiologies of Mitral Valve Regurgitation

Acute

Chronic

  • Rupture chordae tendineae (permits prolapse of a portion of a mitral valve leaflet into the left atrium)

  • Papillary muscle rupture

  • Endocarditis (may lead to valvular destruction)

  • Trauma


Pathogenesis

May also have pulmonary hypertension as a late finding.



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Physical Signs

Hyperdynamic and displaced (downward and to the left) left ventricular impulse

Carotid upstroke diminished in volume but brisk

Holosystolic apical murmur radiating to the axilla and often accompanied by a thrill

S3 heard with a soft S1 and widely split S2

Distended neck veins when severe or acute

Diagnosis

EKG shows signs of left ventricular hypertrophy and left atrial enlargement.

Chest x-ray shows cardiac enlargement, with vascular congestion when the regurgita- tion has led to heart failure.

Echocardiography: The mitral valve can prolapse into the left atrium during systole in cases of a ruptured chordae or mitral valve prolapse. Regardless of the cause, left atrial and left ventricular enlargement occurs if the condition is chronic.

Catheterization is the single most accurate test.

Treatment. With medical therapy, the goal is to relieve symptoms by increasing forward car- diac output and reducing pulmonary venous hypertension.

ARBs or hydralazine

Arteriolar vasodilators (ACE inhibitors)

Digitalis

Diuretics

With surgery, mitral valve replacement is used. Guidelines for selecting patients with mitral regurgitation for operation:

With significantly limiting symptoms and severe mitral regurgitation, surgery is usually indicated. The risk of surgery rises in chronic heart failure.

In patients with regurgitation who have few or no symptoms, surgery should be deferred. Their condition may remain stable for years.

Surgery is indicated when symptoms persist despite optimal medical management.

Criterion is an ejection fraction <60% or left ventricular end systolic diameter >40 mm.

Repair is preferable to replacement.


Mitral Valve Prolapse

Mitral valve prolapse is the most common congenital valvular abnormality (2–3% population) typically seen in young women. It may occur with greater frequency in those with Ehlers-Dan- los syndrome, polycystic kidney disease, and Marfan syndrome.

Most patients are asymptomatic. Lightheadedness, palpitations, syncope, and chest pain may occur (often due to arrhythmias, which may occur.)


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Clinical Pearl

Look for AS in older patients presenting with syncope related to exertion.

Auscultation

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S4 gallop

A2 decreased, S2 single or paradoxically split

Aortic ejection click

Diagnosis. EKG often shows left ventricular hypertrophy. Chest x-ray may present with calcification, cardiomegaly, and pulmonary congestion. Echocardiography shows thick aortic valve leaflets with decreased excursion and LVH.

Treatment. Endocarditis prophylaxis is no longer recommended.

Surgery (valve replacement) is advised when symptoms develop, which is when the valve area is reduced below 0.8 cm2 (normal aortic orifice, 2.5–3 cm2). Generally, if patient has symptoms from stenosis, surgery is the treatment of choice.

Balloon valvuloplasty may be useful in those too ill to tolerate surgery.


Table 5-9. Differential Diagnosis of Aortic Valve Stenosis

Disease Entity

Differentiating Features

Aortic valve sclerosis of the elderly, without stenosis

Systolic murmur does not peak late Carotids do not have delayed upstrokes No left ventricular hypertrophy by EKG

Echocardiographic visualization of excursion of valve leaflets usually normal or mildly reduced, but valves may not be visualized

No hemodynamically significant aortic valve gradient by cardiac catheterization

Hypertrophic obstructive cardiomyopathy

Brisk bifid carotid upstrokes

Murmur usually does not radiate into neck

Characteristic change in murmur with various maneuvers Pseudoinfarct pattern (large septal Q waves) on EKG Characteristic echocardiographic features

Mitral regurgitation

Murmur is holosystolic and radiates to axilla and not carotids

Carotid upstroke may be normal Dilated left ventricle

Aortic valve normal on echocardiogram unless there is associated aortic valve disease

Pulmonic stenosis

Murmur does not radiate into neck; loudest along the left sternal border; increases with inspiration

Physical examination, chest x-ray, and EKG may reveal enlarged right ventricle

Echocardiogram reveals right ventricular enlargement and hypertrophy

Note: All of the above have a systolic murmur that can be confused with aortic stenosis.


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Table 5-10. Effect of Various Maneuvers on Systolic Murmurs



Valsalva

Phenylephrine Handgrip


Squatting

Amyl Nitrite

Leg Raising

Aortic stenosis

Decrease

Decrease

Increase or decrease

Increase

Increase

Hypertrophic obstructive cardiomyopathy

Increase

Decrease

Decrease

Increase

Decrease

Ventricular septal defect

Decrease

Increase

No change

Decrease

Increase

Mitral regurgitation

Decrease

Increase

Increase

Decrease

Increase


Aortic Regurgitation

The most common causes of aortic regurgitation are systemic hypertension and ischemic heart disease.

If mitral regurgitation ensues, the elevated left ventricular diastolic pressure is reflected back to the pulmonary vasculature, and acute pulmonary edema may occur.

Acute aortic regurgitation results in a lower cardiac output, narrower aortic pulse pressure, and a smaller left ventricle than does chronic aortic regurgitation.

Aortic diastolic pressure decreases in chronic aortic regurgitation because of both the regurgitation of blood into the left ventricle and a compensatory decrease in systemic vascular resistance to maintain forward cardiac flow to the periphery. The increased pulse pressure in chronic aortic regurgitation is due to the large stroke volume, causing increased systolic and decreased diastolic pressure.


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Clinical Manifestations

Dyspnea is the most common complaint.

Diastolic decrescendo murmur is the most typical.

Systolic flow murmur

Duroziez sign: systolic and/or diastolic thrill or murmur heard over the femoral arteries

S3 in early left ventricular decompensation

Austin-Flint murmur

Diagnosis

EKG: LV hypertrophy often with volume overload pattern (narrow deep Q waves in left precordial leads)

Chest x-ray: LV and aortic dilation

Echocardiography: Dilated LV and aorta; left ventricular volume overload; fluttering of anterior mitral valve leaflet

Treatment. Endocarditis prophylaxis is no longer recommended.

Salt restriction, diuretics, after load reduction (e.g., ACE inhibitors)

Aortic valve replacement when symptoms worsen or ejection fraction decreases.

Vasodilators such as an ACE, ARB, or nifedipine are the standard of care.

Perform surgery when the ejection fraction is <55% or left ventricular systolic diam- eter is >55 mm.


Clinical Recall

Which of the following is most appropriate in the management of a patient with aortic stenosis?

  1. Warfarin to patients who develop atrial fibrillation

  2. Surgical replacement when the EF <60% or LV end systolic diameter

    >40 mm

  3. Surgical replacement when the valve area <0.8 cm2

  4. Surgical replacement when the EF <55% or LV systolic diameter

    >55 mm

  5. None of the above


Answer: C

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Remember, aortic regurgitation can cause 3 different murmurs



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MYOCARDIAL DISEASE


Cardiomyopathy

Cardiomyopathy is a disease involving the heart muscle itself. Cardiomyopathies can be classified according to morphologic and hemodynamic characteristics.


Table 5-11. Morphologic and Hemodynamic Characteristics of Cardiomyopathies


Dilated

Hypertrophic

Restrictive


Biventricular dilatation

Marked hypertrophy of left ventricle and occasionally of right ventricle; can have disproportionate hypertrophy of septum

Reduced ventricular compliance; usually caused by infiltration of myocardium

(e.g., by amyloid, hemosiderin, or glycogen deposits)

Cardiac output

Normal or

Normal to

Stroke volume

Normal or

Normal or

Ventricular filling pressure

Normal or

Chamber size

Normal or

Normal or

Ejection fraction

Normal to

Diastolic compliance

Normal

Other findings

May have associated functional mitral or tricuspid regurgita- tion.

Obstruction may develop between interventricular septum and septal leaflet of mitral valve.

Characteristic ventricular pressure tracing that resembles those recorded in constrictive pericarditis, with early diastolic dip-and-plateau configuration


Dilated (congestive) cardiomyopathy

Characterized by diminished myocardial contractility, usually involving both ventricles; most common cause for heart transplants.

Etiologies of Dilated (Congestive) Cardiomyopathy


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Peripartum

Postmyocarditis due to infectious agents (viral, parasitic, mycobacterial, Rickettsiae)

Toxins (cobalt, lead, arsenic)

Doxorubicin hydrochloride, cyclophosphamide, vincristine

Metabolic: chronic hypophosphatemia, hypokalemia, hypocalcemia, uremia

Clinical Manifestations. Symptoms and signs of left and right ventricular failure. Typical symptoms of systolic dysfunction.

Diagnosis

X-ray: cardiomegaly with pulmonary congestion

EKG: sinus tachycardia, arrhythmias, conduction disturbances

Echo (key diagnostic study): dilated left ventricle, generalized decreased wall motion, mitral valve regurgitation; transesophageal echo is more sensitive and specific than transthoracic

Catheterization: dilated hypocontractile ventricle, mitral regurgitation

Treatment. Patients are treated as those with systolic heart failure. ACE, beta blockers, and spironolactone lower mortality. Diuretics and digoxin decrease symptoms. Implantable defibrillator may decrease risk of sudden death when the ejection fraction is <35%.


Hypertrophic Obstructive Cardiomyopathy

Etiology. Although hypertrophic obstructive cardiomyopathy (HOCM) can apparently devel- op sporadically, it is hereditary in >60% of cases and is transmitted as an autosomal dominant trait.

An abnormality on chromosome 14 has been identified in the familial form of the disease.

The distinctive hallmark of the disease is unexplained myocardial hypertrophy, usually with thickening of the interventricular septum.

Pathophysiology. As a result of the hypertrophy, left ventricular compliance is reduced, but systolic performance is not depressed. Diastolic dysfunction is characteristic, resulting in decreased compliance and/or inability for the heart to relax.

The heart is hypercontractile, and systole occurs with striking rapidity.

Ejection fractions are often 80–90% (normal is 60%, ±5%), and the left ventricle may be virtually obliterated in systole.

The ability to provoke obstruction or increase/decrease already existing obstruction is influenced by several factors.


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Table 5-12. Factors That Modify Obstruction in Hypertrophic Obstructive Cardiomyopathy

Increase Obstruction

Decrease Obstruction

Mechanism

Physiologic or Pharmacologic Factors

Mechanism

Physiologic or Pharmacologic Factors

Increase in contractility

Tachycardia Digitalis glycosides

β-adrenergic stimulation

(e.g., epinephrine,

exercise) Premature beats

Decrease in contractility

β-adrenergic blockade Heavy sedation and general anesthesia

Calcium channel blockers, disopyramide, and other drugs that depress myocardial function

Reduction in preload

Valsalva maneuver

Decrease in intravascular volume

Increase in preload

Intravascular volume expansion

Squatting


Standing


Bradycardia


Nitroglycerin


β-adrenergic blockade


Vasodilator drugs




Tachycardia



Reduction in afterload

Hypovolemia (diuretics)

Nitroglycerin and related drugs

Increase in afterload

Intravascular volume expansion

Squatting


Vasodilator drugs


α-adrenergic stimulation (e.g., phenylephrine)




Handgrip


Clinical Manifestations


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Treatment

Beta-blockers

Calcium channel blockers that reduce heart rate: diltiazem, verapamil

Disopyramide, occasionally

Use implantable defibrillator if there is syncope

Surgery in severe cases—septoplasty


Restrictive Cardiomyopathy

Restrictive cardiomyopathy is the least common of the causes of cardiomyopathy. It is myocardial disorder characterized by rigid noncompliant ventricular walls.

Etiologies

Infiltrative: sarcoidosis/amyloidosis; hemochromatosis; neoplasia

Scleroderma

Radiation

Pathophysiology. The myocardium is rigid and noncompliant, impeding ventricular filling and raising cardiac filling pressures from abnormal diastolic function. Systolic performance is often reduced, but the overriding problem is impaired diastolic filling, which produces a clinical and hemodynamic picture that mimics constrictive pericarditis.

Clinical Manifestations

Dyspnea, exercise, intolerance, weakness

Elevated jugular venous pressure, edema, hepatomegaly, ascites, S4 and S3 gallop, Kussmaul sign

Diagnosis

X-ray: mild cardiomegaly, pulmonary congestion

EKG: low voltage, conduction disturbances, Q waves

Echo: characteristic myocardial texture in amyloidosis with thickening of all cardiac structures

Catheterization: square root sign; elevated left- and right-sided filling pressures

Treatment. There is no good therapy; ultimately results in death from CHF or arrhythmias; consider heart transplantation.

Clinical Pearl With HOCM, avoid the following:

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Clinical Manifestations. Chest pain, often localized substernally or to the left of the sternum, is usually worsened by lying down, coughing, and deep inspiration (which helps in the differential diagnosis with MI) and is relieved by sitting up and leaning forward.

Pericardial friction rub (diagnostic of pericarditis) is a scratchy, high-pitched sound that has 1 to 3 components corresponding to atrial systole, ventricular systole, and early diastolic ventricular filling. The ventricular systole component is present more consistently. The rub is often transient and is best heard with the diaphragm of the stethoscope as the patient sits forward at forced-end expiration.

Diagnosis. EKG may be diagnostic and reveals a diffuse ST-segment elevation with upright T waves at the onset of chest pain. PR segment depression is very specific. The diffuseness of the


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ST-segment elevation, absence of reciprocal leads, and absence of the development of Q waves

distinguish the characteristic pattern of acute pericarditis from the pattern seen in acute MI.

Treatment of acute pericarditis involves treating its etiology. In idiopathic pericarditis, treat with anti-inflammatory medications (NSAIDs, aspirin, corticosteroids). Adding colchicine to an NSAID decreases recurrence.


Pericardial Effusion

Fluid may accumulate in the pericardial cavity in virtually all forms of pericardial disease. The fluid may be a transudate, as are the serous cavity effusions that develop in patients with CHF, overhydration, or hypoproteinemia. More often, however, the pericardial effusion is an exu- date, reflecting the presence of pericardial injury.

Serosanguineous pericardial fluid is a classic sign in tuberculosis and neoplastic diseases.

Frank blood in the pericardial space may occur in cases of aortic aneurysm or aortic dissection.

Hemopericardium may also be produced by closed or penetrating trauma, rupture of the heart in acute MI, and bleeding caused by coagulation defects.

When fluid accumulates slowly, the pericardium expands to accommodate it. When

fluid accumulates rapidly, however, it compresses the heart and inhibits cardiac filling (cardiac tamponade).

Diagnosis. Echocardiography is the most effective laboratory technique available. The presence of pericardial fluid is recorded as a relatively echo-free space between the posterior pericardium and the posterior left ventricular epicardium in patients with small effusions. In patients with large effusions, the heart may swing freely within the pericardial sac, and this motion may be associated with electrical alternans.

Chest x-ray may show a “water-bottle” configuration of the cardiac silhouette.

Treatment. Treatment includes fluid aspiration and management of the etiology.


Cardiac tamponade

Cardiac tamponade is a life-threatening condition in which a pericardial effusion has devel- oped so rapidly or has become so large that it compresses the heart.

Etiology

Neoplasia

Idiopathic (usually viral) pericarditis

Nonviral infection: tuberculous; suppurative

Intrapericardial hemorrhage with or without pericarditis

Wounds, including surgery of chest; heart; pericardium

Postpericardiotomy syndrome

Uremia

Mediastinal and juxtamediastinal radiation therapy

Vasculitis–connective tissue disease group

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Clinical Manifestations. Most patients with cardiac tamponade complain of dyspnea, fatigue, and orthopnea.

Clinical Manifestations. Most patients complain of dyspnea on exertion due to limited cardiac output. Orthopnea occurs in about 50% of patients. Symptoms and signs related to systemic venous hypertension are often reported: ascites, edema, jaundice, hepatic tenderness, and hepatomegaly (manifestations of right-side failure). Jugular venous distension increases with inspiration (Kussmaul sign). Heart sounds are distant, and an early diastolic apical sound, or “pericardial knock,” is often present and can be confused with an S3 gallop.


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Diagnosis

EKG: low-voltage and nonspecific T-wave changes

Chest x-ray: heart is usually normal in size

Chest CT or MRI: thickened pericardium; pericardial calcifications may be seen in tuberculous constriction

Cardiac catheterization

– Marked “y” descent is present in right atrial pressure tracing

– Characteristic “dip and plateau” or “square root” sign is present in left and right ventricular pressure tracing

– Equalization of end-diastolic pressures in all 4 chambers and pulmonary artery

It is sometimes difficult to distinguish constrictive pericarditis from restrictive cardiomyopa- thy. Left ventricular ejection fraction is more likely to be decreased in the latter. CT is the procedure of choice to demonstrate the thickened pericardium.

Treatment. Treated conservatively at first with mild sodium restriction and diuretics. Pericardiectomy may be needed.


Clinical Recall

Which of the following clinical or diagnostic findings is most specific for the diagnosis of acute pericarditis?

  1. Echocardiography showing ventricular wall thickening with a Kussmaul sign

  2. Echocardiography showing echo-free space between the posterior pericardium and the posterior LV epicardium with distant muffled heart sounds

  3. Cardiac catheterization showing a marked “y” descent in the right atrial pressure tracing with a Kussmaul sign

  4. EKG showing a decrease in SBP >10 mm Hg with normal inspiration

  5. EKG showing diffuse ST-segment elevation with PR segment

depression


Answer: E



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RATE AND RHYTHM DISTURBANCES


Disorders of Sinus Node Function


Sinus bradycardia

Ventricular complexes are normal width, evenly spaced, rate <60/min.

Etiology

Treatment. In the absence of symptoms, no treatment is needed. If symptoms are present, administer atropine acutely. If symptoms and bradycardia still continue, consider a pacemaker.


Atrioventricular block

Atrioventricular (AV) block can be classified in 2 ways: anatomical (based on site of block as determined by His bundle electrocardiography) or clinical (based on the routine ECG). The classic clinical types are first-, second-, and third-degree (or complete) AV block.

First-Degree AV Block

First-degree AV block is pulse rate (PR) interval >0.20 s at heart rate 70 beats/min. It is caused by a cardiomyopathy or by a degenerative change in the AV conduction system due to aging, digitalis, exaggerated vagal tone, ischemia (diaphragmatic infarction, or inflammation (myo- carditis, acute rheumatic fever).

Second-Degree AV Block

See below.


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Table 5-13. Type I versus Type II Second-Degree AV Block


Type I (Mobitz I, Wenckebach)

Type II (Mobitz II)



Mobitz Type I


R R R R


P P P P P


Dropped Beat


Progressive prolongation of the PR interval until a P wave is completely blocked and a ventricu- lar beat is dropped. PR interval of the next conducted beat is shorter than preceding PR interval.


Mobitz Type II

R R R

P

P P


Dropped Beat

Blocked beat occurs suddenly and is not preceded by a change in duration of the PR interval. Patient is equipped with a pacemaker, which cuts in to sustain a regular ventricular rhythm.

Site of block

Usually AV nodal (supra-Hisian)

Infranodal (intra- or infra-Hisian)

QRS complex

Usually normal in width

Usually wide (bundle branch block) with infra- Hisian block; narrow with intra-Hisian block

Causes

Degenerative changes in AV node; diaphragmatic myocardial infarct; digitalis toxicity; myocarditis; rheumatic fever; increased vagal tone

Extensive anterior myocardial infarct; degenera- tive changes in His-Purkinje system; massive calcification of mitral or aortic valve anulus

EKG

PR interval lengthens progressively until ventricu- lar beat is dropped

PR interval shortens after dropped beat

RR interval lengthens progressively up to the dropped beat

PR interval is usually normal in duration and constant in length

if PR interval is prolonged, the duration of prolongation is fixed

Blocked beats occur suddenly without progres- sive lengthening of the PR interval

RR interval of conducted beats is constant or a multiple of a basic RR interval cycle length

Effect of carotid sinus pressure

May increase degree of block

No effect

Effect of atropine

Frequently shortens PR interval and increases AV conduction

No effect

Consequences of

Escape focus usually junctional; narrow QRS

Escape focus infrajunctional (usually ventricular)

progression to

complex; rate >45 beats/min; Adams-Stoke

wide QRS complex; rate <45 beats/min; Adams-

complete heart

attacks uncommon

Stoke attacks common

block





Junctional escape may be present with intra- Hisian block


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Third-Degree (Complete) AV Block

In third-degree (complete) heart block, all atrial beats are blocked, and the ventricles are driven by an escape focus distal to the site of block.


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Figure 5-13. Third-Degree AV Block


The most common cause in adults is simple fibrous degenerative changes in the conduction system as a result of aging (Lenègre disease).

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IV propranolol or esmolol, verapamil

IV digitalis

Synchronized external cardioversion if patient is unstable

Multifocal atrial tachycardia is characterized by an irregular supraventricular rhythm, at rates 100–200 beats/min.

The morphology of the P waves (at least 3 different P wave forms) varies from beat to beat, as does the PR interval. Each QRS complex, however, is preceded by a P wave.

Generally seen in elderly patients or those with chronic lung disease who are experi- encing respiratory failure

Use diltiazem, verapamil, or digoxin; avoid beta blockers because of lung disease

Atrial flutter generally presents as an absolutely regular rhythm with a ventricular rate 125–150 beats/min and an atrial rate 250–300 beats/min (i.e., 2:1 block). It has been associated with:

Chronic obstructive lung disease

Pulmonary embolism

Thyrotoxicosis

Mitral valve disease

Alcohol

Paroxysmal arrhythmia in persons with normal heart

Therapy is cardioversion if hemodynamically unstable (e.g., hypotension), digitalis, verapamil, diltiazem, and beta-blockers.


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Figure 5-14. Atrial Flutter


Atrial Fibrillation

Atrial fibrillation (AF) is the most common sustained cardiac rhythm disturbance. It is associated with heart disease but also occurs with no detectable disease. Thromboembolic events occur with AF and can cause significant morbidity and mortality.


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Figure 5-15. Atrial Fibrillation

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AF is a supraventricular tachyarrhythmia characterized by uncoordinated atrial activation with subsequent decline of atrial function.


CHADS Score

Treatment

0

1

2


When AF is compared with atrial flutter, atrial flutter is found to be more organized than AF, with a sawtooth pattern of regular atrial activation called flutter (f) waves on the ECG, particularly visible in leads II, III, and aVF.

The diagnosis of AF should be considered in elderly patients who present with complaints of shortness of breath, dizziness, or palpitations. The arrhythmia should also be suspected in patients with acute fatigue or exacerbation of CHF. In some patients, AF may be identified on the basis of an irregularly irregular pulse or ECG obtained for another condition.



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New onset AF


Hemodynamically stable

(no hypotension, no acute heart failure, etc.)


Yes

No


Control rate (<110 beats/min) with diltiazem, verapamil, beta-blocker, or digoxin

Cardioversion: sedate before (100J, 200J, 300J

until sinus rhythm returns)



Spontaneous conversion to SR

Consider anticoagulation after patient is stable



Yes

No


Assess cause and follow-up

Consider cardioversion (electrical or pharmacologic)


AF recurs


AF >48 hours


Yes

No or

questionable



AF persists

Observe off anticoagulation



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Figure 5-16. Management of Atrial Fibrillation (AF)


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Cardiac conditions commonly associated with the development of AF include rheumatic mitral valve disease, coronary artery disease, CHF, and hypertension (cause atrial structures to dilate). Noncardiac conditions which can predispose patients to develop AF include hyperthy- roidism, hypoxemia, and alcohol intoxication.

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Note

Routine rhythm control for AF is not indicated. It is an exception.

Evaluation of Patients with AF (Minimum Workup):

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Catheter ablation of AF foci is sometimes used as one of the nonpharmacologic therapies for eradicating AF. The techniques evolved with the demonstration that most AF is initiated by ectopic beats from focal areas that may be targeted for ablation. These foci arise more commonly from the 4 pulmonary veins. Thus, techniques have focused on the identification and elimination of these foci.

Ventricular rate control to achieve a rate of <100–110 beats/min is one of the first steps in managing AF. Beta blockers, calcium channel blockers, and digoxin are the drugs most commonly used for rate control. These agents do not convert atrial fibrillation to sinus rhythm and should not be used for that purpose. Beta blockers and calcium channel blockers are effective in reducing the heart rate at rest and during exercise in patients with AF. Digoxin, because of the inotropic effects, is the drug of choice in patients with coexisting systolic heart failure. Factors that should guide drug selection include the patient’s medical condition and the presence of concomitant heart failure. The following drugs are recommended for their demonstrated efficacy in rate control at rest and during exercise: diltiazem, atenolol, metopro- lol, and verapamil.

Rate control with chronic anticoagulation is the recommended strategy for the majority of patients with chronic AF. Rhythm control has not been shown to be superior to rate control (with chronic anticoagulation) in reducing morbidity and mortality.

Control the heart rate, then anticoagulate. Use aspirin for those with CHADS 0 or 1, and dabigatran, rivaroxaban, or warfarin for CHADS 2 or more. Heparin is not necessary prior to starting oral anticoagulants.

Patients with AF should receive chronic anticoagulation with dabigatran, rivaroxaban, or adjusted-dose warfarin, unless they have a specific contraindication.

The goals of initial management are hemodynamic stabilization, ventricular rate control, and prevention of embolic complications. When AF does not terminate spontaneously, the ventricular rate should be treated to slow ventricular response and anticoagulation started.


Pre-excitation syndrome

Wolff-Parkinson-White Syndrome (WPW)

Pre-excitation is a condition in which all or some portion of the ventricle is activated by atrial impulses earlier than if the impulses were to reach the ventricles by way of the normal cardiac conduction pathways. This is achieved by the use of accessory pathways (Kent bundle).

Clinical Presentation. Patients with long QT interval are prone to recurrent dizziness or syncope from the ventricular tachycardia.

Sudden auditory stimuli, such as the ringing of the telephone at night, may initiate Torsade de Pointes in a vulnerable individual with a long QT interval syndrome.

Treatment. Treat the underlying disorder. In the case of the antiarrhythmics, use a drug such as lidocaine. With electrolyte imbalance disorders, replace potassium and magnesium. Cardiac pacing or isoproterenol infusion may suppress episodes of tachycardia, useful for emergency treatments. If hemodynamically unstable (e.g., hypotension), consider cardioversion (but this

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Ventricular Fibrillation

See the Emergency Medicine section.


1

Pulseless Arrest

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3 2 9

VF/VT

Check rhythm

Shockable rhythm?

Asystole/PEA

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Give 1 shock

Resume CPR


Give 5 cycles of CPR*

4 image

Resume CPR immediately for 5 cycles

When IV/IO available, give vasopressor

Repeat every 3 to 5 min

or



Give 5 cycles of CPR*

10


5 image

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Check rhythm

Shockable rhythm?

No


Continue CPR while defibrillator is charging

Give 1 shock

Resume CPR immediately after the shock

When IV/IO available, give vasopressor during CPR (before or after the shock)

Repeat every 3 to 5 min

or



Give 5 cycles of CPR*

6 image Shockable

Check rhythm

Shockable rhythm?


Not shockable


Shockable


13


11 image


12 image image

Go to Box 4


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Check rhythm

Shockable rhythm?

7 No

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Shockable

8

Clinical Presentation. The symptoms of anemia tend to be based on the severity of the anemia rather than the specific etiology. Early symptoms include fatigue and poor exercise tolerance. As the anemia worsens, there is dyspnea on exertion and lightheadedness. Eventually, confusion and altered mental status may develop as oxygen delivery to the brain decreases. Death from anemia is most often caused by decreased oxygen delivery to the heart and resulting myocardial ischemia.


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The severity of symptoms is related to the underlying condition of the patient. A healthy young patient may have no symptoms at all with hematocrit 27–29%, whereas an older patient with heart disease may develop dyspnea or anginal symptoms with the same hematocrit.

Diagnosis. Once a diagnosis of anemia is determined based on a low hematocrit or hemoglo- bin, the first step is to determine the MCV. Iron studies, reticulocyte count, peripheral smear, red cell distribution width (RDW), Coombs test, vitamin B12, folate level, and even a possible bone marrow biopsy may be necessary to determine a specific etiology.

Treatment. Besides blood transfusion, treatment cannot be generalized. Packed RBCs are used to maintain a hematocrit >25–30%. This is based on the underlying condition of the patient. A healthy young patient can have transfusion withheld until hematocrit is in the low 20%. An older patient with coronary artery disease will need to be maintained when hematocrit >30%. Hematocrit should rise approximately 3 points for every unit of packed RBCs given. Whole blood is rarely, if ever, used.


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MCV 80−100

Check Reticulocyte Count

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MCV >100

Anemia

Hct <41% <36%

Hb <13.5 g/dL <12 g/dL

MCV <80

Macrocytic Anemia

Microcytic Anemia

Check MCV

Chapter 6 Hematology



Reticulocyte Count <3% (bad bone marrow response)

Reticulocyte Count >3% (good bone marrow response)


Normocytic Anemia


Intravascular Hemolysis

• Hemoglobinuria

• Decreased haptoglobin

Extravascular Hemolysis

• Jaundice

• Increased unconjugated bilirubin

• Pigment stones

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Figure 6-1. Evaluation of Patients with Anemia


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Clinical Pearl

In early iron deficiency, serum iron may be normal. (Ferritin is low and TIBC is elevated.)

MICROCYTIC ANEMIA


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Iron Deficiency Anemia

Iron deficiency anemia is anemia with diminished RBC production and MCV <80, character- ized by hypochromic cells and low levels of stored iron. It is almost always caused by blood loss, most commonly GI or menstrual.

Iron absorption is tightly regulated. A man requires 1 mg per day and a woman 2–3 mg per day on average. It is difficult for the body to increase the level of iron absorption. If there is even a modest increase in blood loss—occult blood in the stool, heavier menstrual flow, or increased demand such as in pregnancy—the body is poorly equipped to increase its level of absorption to exceed 3–4 mg per day. Other etiologies are increased urinary loss of blood, mal- absorption, hemolysis, and poor oral intake.

Clinical Presentation. Mild anemia may have no or very limited symptoms. As hematocrit approaches 30%, fatigue and poor exercise tolerance may develop. As hematocrit lowers to 25%, tachycardia, palpitations, dyspnea on exertion, and pallor develop. Older patients and those with coronary artery disease may become dyspneic at higher levels of hematocrit. More severe anemia results in lightheadedness, confusion, syncope, and chest pain. A systolic ejection murmur (“flow” murmur) may develop in any patient with moderately severe anemia. These symptoms are not specific for iron deficiency anemia and may develop with any form of anemia provided it is sufficiently severe.

Symptoms specific to iron deficiency are rare and cannot be relied upon to determine the diagnosis: brittle nails, spoon-shaped nails, glossitis, and pica. Iron deficiency anemia as a specific diagnosis is determined by laboratory findings, not symptoms.

Diagnosis. A low serum ferritin <10 ng/mL is the most characteristic finding of iron deficien- cy anemia. Low ferritin has good specificity (>99%) but poor sensitivity (60%); the ferritin level may be falsely elevated because it is an acute phase reactant and may be elevated in other inflammatory states or with malignancy. MCV is low except in very early cases. The serum iron is low and the total iron binding capacity is high. The RDW is elevated. The most specific test, although rarely necessary, is a bone marrow biopsy looking for stainable iron stores. The reticulocyte count is low. Platelet levels rise.

Treatment. Treatment usually includes oral therapy with ferrous sulfate tablets, continued until Hb and Ht have normalized and an additional 2-3 months to “restore” iron stores. With replacement of iron, a brisk increase in reticulocytes will be seen 2 weeks into treatment. Parenteral iron is used in patients with malabsorption, kidney disease, or an intolerance to oral therapy. Blood transfusion is the most effective way to deliver iron but is reserved for those with severe symptoms.


Anemia of Chronic Disease

Anemia of chronic disease is a defect in the body’s ability to make use of iron sequestered in stores within the reticuloendothelial system. It can be microcytic or normocytic. Anemia can accompany virtually any chronic inflammatory, infectious, or neoplastic condition. Hepcidin, a regulator of iron metabolism, plays an important role in anemia of chronic disease. In states where hepcidin level is abnormally high (e.g., inflammation), serum iron falls due to iron trap- ping within macrophages and liver cells and decreased gut iron absorption. This typically leads to anemia caused by an inadequate amount of serum iron being available for developing red cells.


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Clinical Presentation. Symptoms are based on the severity of the anemia. The only other symptoms are based on the specifics of the underlying disease.

Diagnosis. Serum ferritin level is normal or elevated. Serum iron level and total iron binding capacity (TIBC) are both low. Reticulocyte count is low.

Treatment. Correct the underlying disease. Iron supplementation and erythropoietin will not help, except in renal disease and anemia caused by chemotherapy or radiation therapy.


Sideroblastic Anemia

Sideroblastic anemia is a microcytic anemia caused by a disorder in the synthesis of hemoglobin, characterized by trapped iron in the mitochondria of nucleated RBCs. There are both hereditary and acquired forms. The hereditary form is due to a defect in aminolevulinic acid synthase or an abnormality in vitamin B6 metabolism. The acquired form is due to drugs such as chloram- phenicol, isoniazid, or alcohol. Lead poisoning can cause sideroblastic anemia as well.

There is an association with myelodysplastic syndromes and refractory anemia. Sideroblastic anemia may progress to acute myelogenous leukemia in a small percentage of patients.

Clinical Presentation. Symptoms are related to the severity of the anemia. There is no specific finding that will be sufficiently suggestive of sideroblastic anemia to allow a diagnosis without significant lab evaluation.

Diagnosis. Serum ferritin level is elevated. Transferrin saturation is very high, and thus TIBC is very low. Serum iron level is high. The most specific test is a Prussian Blue stain of RBCs in the marrow that will reveal the ringed sideroblasts. Marrow reticuloendothelial iron is strikingly increased. Sideroblastic anemia is the only microcytic anemia in which serum iron is elevated.

Treatment. Remove the offending drug. Some patients, especially those with INH-associated sideroblastic anemia, will respond to pyridoxine therapy 2-4 mg per day. Consider transfusion for serious cases and BMT for refractory cases.


Clinical Pearl

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Both iron deficiency and anemia of chronic disease may have decreased serum iron.



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Figure 6-2. Basophilic Stippling, a Feature of Lead Poisoning and Other Diseases


Thalassemia

Thalassemia is a hereditary underproduction of either the alpha or beta globin chains of the hemoglobin molecule, resulting in a hypochromic, microcytic anemia. Gene deletion results in variable levels of disease. There are 4 genes coding for the alpha chain of hemoglobin.

There can be deletions of 1, 2, 3, or all 4 genes.



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– Patients with beta thalassemia major (or Cooley’s anemia) are homozygous for mutations of both genes coding for the beta hemoglobin gene. Patients become severely symptomatic starting age 6 months, when the body would normally switch from fetal hemoglobin to adult hemoglobin. They are severely symptomatic with growth failure, hepatosplenomegaly, jaundice, and bony deformities secondary to extramedullary hematopoiesis. They are later symptomatic from hemochromatosis, cirrhosis, and CHF from chronic anemia and transfusion dependence.

Diagnosis. Clues to the diagnosis of thalassemia trait is a mild anemia with a profound microcytosis. Beta thalassemia major has the severe symptoms, large spleen, and bone abnormalities described. Both forms of thalassemia are diagnosed by having a microcytic anemia with normal iron studies. Hemoglobin electrophoresis differentiates which type of thalassemia is present. In beta thalassemia, there is an increased level of hemoglobin F and hemoglobin A2. In beta thalassemia major, the hemoglobin is as low as 3–4 g/dL. Those with

alpha thalassemia will have normal amounts of hemoglobins F and A2. Tetrads of beta chains

are called hemoglobin H. Hemoglobin H is present in alpha thalassemia with 3 of 4 genes

deleted. Target cells are present in all forms of thalassemia trait and thalassemia major. The RDW is normal in all forms because all of the cells are of the same size.

Treatment. Thalassemia traits of both the alpha and beta types do not require specific treat- ment. Beta thalassemia major patients require blood transfusions once or twice a month. The chronic transfusions lead to iron overload, which requires treatment with deferasirox. Oral deferasirox is the standard of care. This is easier to give than deferoxamine, which requires a subcutaneous pump. Splenectomy eliminates a major area of hemolysis and therefore helps reduce transfusion requirements. A small number of patients can be treated with a bone marrow transplantation.


Table 6-1. Iron Indices in Microcytic Anemia Syndromes


Clinical Pearl Thalassemia trait syndromes are asymptomatic.



Fe Panel


Iron Deficiency Anemia

Anemia of Chronic Disease


Sideroblastic Anemia


Thalassemia Minor

Serum Iron

Decreased

Decreased

Increased

Normal

Serum Ferritin

Decreased or Normal (early)

Increased

Increased

Normal

Transferrin/ TIBC

Increased

Decreased

Decreased

Normal

% Saturation

Decreased

N/ Decreased

Increased

Normal



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Clinical Recall

Which of the following laboratory investigations has the highest specificity and sensitivity in the diagnosis of iron deficiency anemia?

  1. Serum ferritin level

  2. Serum iron level

  3. Serum TIBC

  4. Serum MCV

  5. Bone marrow biopsy


Answer: E


MACROCYTIC ANEMIA

A 72-year-old alcoholic man comes to the office with several weeks of memory loss and tingling in his feet. His hematocrit is 32% and MCV 110.


Vitamin B12 (Cyanocobalamine) Deficiency

Vitamin B12 deficiency is decreased absorption or intake of vitamin B12, resulting in hematologic and/or neurologic abnormalities. The most common cause is pernicious anemia, a disorder causing decreased intrinsic factor production due to autoimmune destruction of parietal cells. The incidence of pernicious anemia increases with age. Gastrectomy and atrophic gastritis can also decrease intrinsic factor production. Various forms of malabsorption such as sprue, regional enteritis, and blind loop syndrome can block absorption of vitamin B12.

Pancreatic insufficiency can result in the inability to absorb the vitamin. Rarely, tapeworm infection with Diphyllobothrium latum can decrease absorption. Decreased intake is unusual and requires several years to produce disease.

Clinical Presentation. Manifestations vary with the severity of the anemia. As such, you cannot specifically determine that a patient has B12 deficiency only from the symptoms of anemia.

Neurologic manifestations may involve almost any level of the neurologic system. Patients may have peripheral neuropathy, position sense abnormality, vibratory, psychiatric, autonomic, motor, cranial nerve, bowel, bladder, and sexual dysfunction. Glossitis, diarrhea, and abdominal pain may occur. You may have either the hematologic or neurologic deficits individually or combined.

Diagnosis. Anemia with macrocytosis (increased MCV). A smaller number of patients may have the neurologic deficits alone. The WBCs have hypersegmented neutrophils with a mean lobe count >4. The red cells are characterized by macro-ovalocytes. Although macrocytosis can occur with hemolysis, liver disease, and myelodysplasia, these give round macrocytes. B12 and folate deficiency produce oval macrocytes. The hematologic pattern of vitamin B12 deficiency is indistinguishable from folate deficiency. The reticulocyte count is reduced, although the bone marrow is hypercellular. Pancytopenia may occur. An elevated LDH, bilirubin, and iron level may occur and are due to mild hemolysis of immature erythrocytes.


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The most specific test is a low B12 level. Antibodies to intrinsic factor and parietal cells confirm the etiology as pernicious anemia. The Schilling test is rarely used to determine the etiology of vitamin B12 deficiency. It is not necessary if the patient has a low B12 level com- bined with the presence of antibodies to intrinsic factor. An elevated methylmalonic acid level occurs with B12 deficiency and is useful if the B12 level is equivocal.

Treatment. Replace the vitamin B12 lifelong. Options available for treating clinical vitamin B12 deficiency include oral (daily) and parenteral (monthly intramuscular or subcutane- ous) preparations. Parenteral route is recommended for patients with neurologic manifesta- tions of B12 deficiency. IV dosing is not recommended because that would result in most of the vitamin being lost in the urine.

Response of vitamin B12 deficiency anemia to treatment is usually rapid, with reticulocytosis occurring within 2–5 days and hematocrit normalizing within weeks. Treatment with cobala- min effectively halts progression of the deficiency process but might not fully reverse more advanced neurologic effects. If the underlying cause of the vitamin B12 deficiency is treatable (e.g., fish tapeworm infection or bacterial overgrowth), then treatment should include address- ing the underlying etiology.

Patients who have vitamin B12 deficiency with associated megaloblastic anemia might experience severe hypokalemia and fluid overload early in treatment due to increased erythro- poiesis, cellular uptake of potassium, and increased blood volume. Once treated for a vitamin B12 deficiency due to pernicious anemia or other irreversible problems with absorption, patients need to continue some form of cobalamin therapy lifelong.

Folic acid replacement can correct the hematologic abnormalities of B12 deficiency, but not the neurologic abnormalities.


Folic Acid Deficiency

Folic acid deficiency is almost always caused by some form of decreased dietary intake. It can lead to anemia. Occasionally, increased requirements from pregnancy, skin loss in diseases like eczema, or increased loss from dialysis and certain anticonvulsants such as phenytoin may occur. Con- sumption of high amounts of alcohol may have a direct effect on the folate absorption, due to inhibition of the enzyme intestinal conjugase. Folate is presented in foods as polyglutamate, which is then converted into monoglutamates by intestinal conjugase.

Clinical Presentation. Presentation depends entirely on the severity of the anemia.

Diagnosis. The hematologic presentation of folic acid deficiency is identical to B12 deficiency. The diagnosis is based on a low red-blood-cell, folic-acid level.

Treatment. Replace folic acid, almost always orally.


HEMOLYTIC ANEMIA

Hemolytic anemias are caused by decreased RBC survival from increased destruction of the cells. The destruction may be inside the blood vessels (intravascular) or outside (extravascular), which generally means inside the spleen. Hemolytic anemia may be chronic (sickle cell disease, paroxys- mal nocturnal hemoglobinuria, and hereditary spherocytosis) or acute (drug-induced hemolysis, autoimmune hemolysis, or glucose 6-phosphate dehydrogenase deficiency).


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Table 6-2. Classification of Hemolytic Anemias

Hereditary Anemias

Acquired Anemias

Membrane: hereditary spherocytosis, hereditary elliptocytosis

Immune

  • Autoimmune: warm antibody type, cold antibody type

  • Alloimmune: hemolytic transfusion reactions, hemolytic disease of the newborn, allografts (especially stem cell transplantation)

  • Drug-associated

Metabolism: G6PD deficiency, pyruvate kinase deficiency

Red Cell Fragmentation Syndromes

Hemoglobin: genetic abnormalities (Hb S, Hb C, unstable)

Infections: malaria, clostridia


Chemical and Physical Agents: drugs, indus- trial/domestic substances, burns


Secondary: liver and renal disease


Paroxysmal Nocturnal Hemoglobinuria


Clinical Presentation. The usual symptoms of anemia are present based on the severity of the disease, not necessarily the etiology. Fatigue and weakness occur with mild disease. Dyspnea and later confusion occur with more severe disease. The major difference between hemolytic anemia and the micro- and macrocytic anemias is that hemolysis is more often the etiology when the onset is sudden. This is, of course, provided that simple blood loss has been exclud- ed. Hemolysis is often associated with jaundice and dark urine as well. Specific findings associated with each disease are described below. Fever, chills, chest pain, tachycardia, and backache may occur if the intravascular hemolysis is particularly rapid.

Diagnosis. Patients with hemolytic anemias generally have a normal MCV, but the MCV may be slightly elevated because reticulocytes are somewhat larger than older cells. The reticulocyte count is elevated. The LDH and indirect bilirubin are elevated. Bilirubin levels above 4 are unusual with hemolysis alone. The peripheral smear may aid in the specific diagnosis, and the haptoglobin may be low with intravascular hemolysis. Hemoglobin may be present in the urine when intravascular hemolysis is sudden and severe because free hemoglobin spills into the urine. There should not be bilirubin in the urine because indirect bilirubin is bound to albumin and should not filter through the glomerulus. Hemosiderin is a metabolic product of hemoglobin. Hemosiderin may be present in the urine if the hemolysis is severe and lasts for several days.

Treatment. Transfusion is needed as in all forms of anemia when the hematocrit becomes low. Hydration is, in general, useful to help prevent toxicity to the kidney tubule from the free hemo- globin. Specific therapy is discussed with each disease below. Patients with chronic hemolytic anemia need to be maintained on chronic folic acid therapy, as there is an increase in cell turnover.


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Sickle Cell Disease

Sickle cell disease is a hereditary form of chronic hemolysis, ranging from asymptomatic to severe, overwhelming crisis. It is characterized by irreversibly sickled cells and recurrent painful crises.

Clinical Presentation. Chronic manifestations include renal concentrating defects (isosthenuria), hematuria, ulcerations of the skin of the legs, bilirubin gallstones, aseptic necrosis of the femoral head, osteomyelitis, retinopathy, recurrent infections from Pneumococ- cus or Haemophilus, growth retardation, and splenomegaly followed in adulthood by autosple- nectomy. The acute painful crisis consists of back, rib, chest, and leg pain. Occasionally some patients will have very severe and life-threatening manifestations of sickling. These include the acute chest syndrome consisting of severe chest pain, fever, leukocytosis, hypoxia, and infil- trates on the chest x-ray. The acute chest syndrome is indistinguishable from pneumonia.

Stroke and TIA may also occur. Priapism can occur from infarction of the prostatic plexus of veins. Blindness and even myocardial infarction and cardiomyopathy may also occur. Pregnant patients experience increased rates of spontaneous abortion and low birth weight.

Sickle trait gives normal hematologic picture with no anemia and a normal MCV. The only significant manifestation of trait is the renal concentrating defect presenting with isosthenuria and microscopic hematuria. Sickle trait also increases the frequency of UTI. Those with trait will rarely develop the acute pain crisis under conditions of profound hypoxia and acidosis.


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Figure 6-3. Sickle Cells Noted on a Peripheral Blood Smear


Diagnosis. Patients with sickle cell disease typically have a mild to moderate anemia with a normal MCV. The reticulocyte count should always be elevated in the 10–20% range unless they have folate deficiency or Parvovirus B19 aplastic crisis. LDH and bilirubin are elevated as

in all types of hemolytic anemias. The hemoglobin electrophoresis is the most specific test. The

peripheral smear shows sickled cells. The sickle prep (or Sickledex) is a quick screening test used to diagnose evidence of sickle cell trait and cannot distinguish between trait and homozy- gous disease. The urinalysis usually has blood present, although it is often microscopic. The white blood cell count is often elevated in the 10,000–20,000 range, although this can also indicate the presence of infection.

Treatment. An acute sickle cell pain crisis is treated with fluids, analgesics, and oxygen. Antibiotics are given with infection or even to patients with fever and leukocytosis even if a definite site of infection has not been documented. Ceftriaxone is the preferred agent because it covers Pneumococcus and Haemophilus influenza. Severe or life-threatening manifestations such as acute chest syndrome, CNS manifestations, priapism, and acute cardiac manifestations are managed with red blood cell transfusions if the hematocrit is low, and exchange transfusion if the hematocrit is high. Chronic management includes folic acid replacement and vaccinations against Pneumococcus and influenza. Hydroxyurea is used to decrease the frequency of the

vaso-occlusive pain crisis. Bone marrow transplantation can be curative in severe cases.


Autoimmune, Cold Agglutinin, and Drug-Induced Hemolytic Anemia

Various forms of acquired hemolytic anemias can result from the production of IgG, IgM, or activation of complement C3 against the red cell membrane. They are often sudden and idiopathic. The lysis can be intravascular or extravascular (far more common). That is because

the destruction of the cells most often occurs through macrophages in the spleen or by Kupffer cells in the liver.


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Autoimmune destruction is often idiopathic. Known causes of autoimmune destruction are from antibodies produced in relationship to various forms of leukemia, especially chronic lymphocytic leukemia, viral infections, lymphoma, collagen vascular diseases like lupus, or in relationship to drugs. The most common drugs are the penicillins, cephalosporins, sulfa drugs, quinidine, alpha-methyldopa, procainamide, rifampin, and thiazides.

Ulcerative colitis can also lead to autoimmune hemolytic anemia. Cold agglutinin disease is an IgM antibody produced against the red cell in association with malignancies such as lymphoma or Waldenstrom macroglobulinemia and infections such as Mycoplasma or mononucleosis. Cold agglutinin destruction occurs predominantly in the liver. Liver-mediated destruction is not affected by steroids. Up to 50% of patients do not have an associated underlying disorder.

Clinical Presentation. Symptoms are generally related to the severity of the anemia, not the etiology. The onset may be very sudden resulting in fever, syncope, congestive failure, and hemoglobinuria. Mild splenomegaly is present when the disease has been occurring long enough for the time it takes for the spleen to enlarge. The drug history is often the clue with drug-induced varieties. Cold agglutinin disease results in cyanosis of the ears, nose, fingers, and toes. Weakness, pallor, jaundice, and dark urine may occur as it can in all forms of hemolysis of sufficient severity.

Diagnosis. Autoimmune hemolysis gives a normocytic anemia, reticulocytosis, increased LDH, absent or decreased haptoglobin, and increased indirect bilirubin, as can all forms of hemolysis. The Coombs test is the specific test that diagnoses autoimmune, cold agglutinin, and often even drug-induced hemolysis. Spherocytes are often present on the smear.


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Figure 6-4. Acanthocytes, a Feature of Several Hematologic and Systemic Diseases


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Treatment. Mild disease often occurs, which needs no treatment. In cases of drug-induced hemolysis, stop the offending drug. More severe autoimmune hemolysis is treated with steroids first. Splenectomy is done for those unresponsive to steroids. Cold agglutinin disease is primar- ily managed by avoiding the cold. Most cases of cold agglutinin disease are mild, but in those who have severe disease despite conservative measures, azathioprine, cyclosporine, or cyclo- phosphamide can be used. Rituximab is also useful. This is an anti-CD20 antibody. Steroids and splenectomy don’t work well with cold agglutinin disease because the destruction occurs in the liver. You need to control the lymphocytes which control the production of IgM.


Hereditary Spherocytosis

Hereditary spherocytosis is a chronic mild hemolysis with spherocytes, jaundice, and spleno- megaly from a defect in the red cell membrane. It is an autosomal dominant disorder where the loss of spectrin in the red cell membrane causes the red cell to form as a sphere, rather than as a more flexible and durable biconcave disc. Hemolysis occurs because the spheres are not able to pass the narrow passages in the spleen.

Clinical Presentation. A chronic disorder with mild to moderate symptoms of anemia. Because the hemolysis occurs in the spleen, there is often splenomegaly and jaundice. Severe anemia occasionally occurs from folate deficiency or Parvovirus B19 infection such as in sickle

cell disease. Bilirubin stones often occur, leading to cholelithiasis, often at a young age.

Diagnosis. A normal to slightly decreased MCV anemia with the elevated LDH; indirect bilirubin and reticulocyte count similar to any kind of hemolysis. Although spherocytes may be present with autoimmune hemolysis, hereditary spherocytosis has a negative Coombs test. The cells have increased sensitivity to lysis in hypotonic solutions known as an osmotic fragility test. The mean corpuscular hemoglobin concentration (MCHC) is elevated.

Treatment. Most patients require no treatment beyond folate replacement chronically. In those with more severe anemia, removal of the spleen will eliminate the site of the hemolysis. The symptoms and jaundice will resolve but the spherocytes will remain.


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Figure 6-5. Features of Hereditary Spherocytosis Seen on Peripheral Blood Smear


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Paroxysmal Nocturnal Hemoglobinuria

Paroxysmal nocturnal hemoglobinuria (PNH) is a red cell membrane defect leading to intermittent dark urine and venous thrombosis and a chronic form of hemolysis. A red cell membrane defect in phosphatidyl-inositol glycan A (PIG-A) allows increased binding of complement to the red cell, leading to increased intravascular hemolysis. It is a clonal stem-cell disorder, and so can develop into aplastic anemia and leukemia. The cells are more susceptible to lysis by complement in an acid environment. Everyone becomes a little acidotic at night because of a relative hypoventilation.

Clinical Presentation. In addition to symptoms of anemia, these patients characteristically present with dark urine from intravascular hemolysis. Thrombosis of major venous structures, particularly the hepatic vein (Budd-Chiari syndrome), is a common cause of death in these patients. The hemoglobinuria is most commonly in the first morning urine because the hemolysis occurs more often when patients develop a mild acidosis at night.

Diagnosis. Besides the usual lab findings of hemolysis, such as an increased LDH, bilirubin, and reticulocyte count, these patients have brisk intravascular hemolysis and therefore have a low haptoglobin and hemoglobin in the urine. Hemosiderinuria occurs when the capacity of renal tubular cells to absorb and metabolize the hemoglobin is overwhelmed, and the sloughed off iron-laden cells are found in the urine. The gold standard test is flow cytometry for CD55 and CD59 on white and red cells. In PNH, levels are low or absent.

Treatment. Treatment for PNH depends on the severity of symptoms. Some patients with few or no symptoms require only folic acid and possible iron supplementation. Over time, the dis- ease may progress and thus require more aggressive care.

PNH is often associated with bone marrow failure. Occasionally patients will respond to antithymocyte globulin, but frequently they will continue to require red cell and/or platelet transfusions. Allogeneic bone marrow transplantation has been the mainstay of curative therapy for PNH. Recently, the drug eculizumab (brand name Soliris) was approved by the FDA to treat symptoms of the disease.


Glucose-6-Phosphate Dehydrogenase Deficiency

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a hereditary deficiency of an enzyme for producing the reducing capacity necessary for neutralizing oxidant stress to the red cell resulting in acute hemolysis.

Various forms of oxidant stress result in sudden hemolysis. The most common type of oxidant stress is actually from infections, not drugs. The most commonly implicated drugs are sulfa drugs, primaquine, dapsone, quinidine, and nitrofurantoin.

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Decay accelerating factor (DAF) is also known as CD55 and CD59. DAF are the main proteins that protect RBCs from complement destruction.


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Clinical Presentation. Patients are normal until exposed to the stress. A sudden, severe, intravascular hemolysis can occur including jaundice, dark urine, weakness, and tachycardia. The history of recent drug ingestion is the main clue to the diagnosis.

Diagnosis. The usual findings of an intravascular hemolysis include high LDH, bilirubin, and reticulocyte count with a normal MCV, low haptoglobin, and hemoglobinuria. Heinz bodies are precipitated hemoglobin inclusions seen in red cells. Bite cells are seen on smear indicat- ing the removal of the Heinz bodies. The definitive test is the G6PD level, which can be falsely normal immediately after an episode of hemolysis. Hence, the level is best tested about 1 week after the event.

Treatment. There is no specific therapy beyond hydration and transfusion if the hemolysis is severe. The main therapy is to avoid oxidant stress in the future.


Clinical Recall

Which of the following clinical scenarios is an indication for an exchange transfusion in a patient with sickle cell anemia?

  1. Acute chest syndrome with a low hematocrit

  2. Priapism with a normal hematocrit

  3. Pneumococcal sepsis with an elevated hematocrit

  4. Focal neurological deficits with an elevated hematocrit STEMI with a normal hematocrit


Answer: D


APLASTIC ANEMIA

Aplastic anemia is failure of all 3 cell lines produced in the bone marrow, resulting in anemia, leukopenia, and thrombocytopenia (pancytopenia). The marrow is essentially empty with the absence of precursor cells. Many things can cause bone marrow failure, but the most common cause of true aplastic anemia is not often determined. Radiation, toxins such as benzene, drugs such as NSAIDs, chloramphenicol, alcohol, and chemotherapeutic alkylating agents can all cause aplastic anemia. Infiltration of the marrow with infections such as tuberculosis or cancer such as lymphoma can cause pancytopenia, but that is not truly aplastic anemia. Aplastic anemia can also be caused by infections such as hepatitis, HIV, CMV, Epstein-Barr virus, or Parvovirus B19 in immunocompromised patients.

Clinical Presentation. Patients typically present with bleeding from the thrombocytopenia, and possibly with a combination of the findings associated with deficiencies in all 3 cell lines. Fatigue from anemia and infections from neutropenia may also occur. The clinical presenta- tion may give a clue to the presence of pancytopenia but is not sufficient to determine a true aplastic anemia by clinical manifestations alone. The absence of a classical association such as benzene, radiation, or chloramphenicol would most certainly not exclude a diagnosis of aplastic anemia. The most common single etiology is idiopathic.

Diagnosis. Pancytopenia on a CBC is the first test. A bone marrow biopsy confirms the diagno- sis when alternative etiologies for a pancytopenia are not present. In other words, the marrow is


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empty of almost all precursor cells as well as evidence of primary or metastatic cancer, infection, or fibrosis. The marrow is hypoplastic and fat filled with no abnormal cells seen.

Treatment. Treatment includes bone marrow transplant when the patient is young and healthy enough to withstand the procedure and there is a donor available (cure rate is 80–90% of patients age <50).

When bone marrow transplant is not possible, try immunosuppressive agents: a combination of antithymocyte globulin, cyclosporine, and prednisone (can lead to remission in 60–70% of patients). It is believed that T lymphocytes are primarily causal in the bone marrow failure, so drugs are used to decrease the T-cell response.


ACUTE LEUKEMIA

Acute leukemia is the rapid onset of bone marrow failure from the derangement of the pluripotent stem cell, causing the relentless destruction of the normal production of the entire bone marrow. Blood cells lose their ability to mature and function normally. Most cases of acute leukemia arise with no apparent cause, but there are several well known associations: radiation exposure, benzene, chemotherapeutic agents such as melphalan and etoposide, and some retroviruses.

Genetic disorders such as Down syndrome and Klinefelter can cause an increased incidence of leukemia. Myelodysplasia and sideroblastic anemia can also develop into acute leukemia.

Clinical Presentation. Patients typically present with the effects of the leukemic blast cells crowding out the normal marrow cells, leading to symptoms of bone marrow failure (even if total WBC count is elevated or normal). Fatigue from anemia is the most common presenting complaint. Bleeding from thrombocytopenia occurs. Infection from the underproduction or abnormal function of WBCs also occurs.

Acute lymphocytic leukemia (ALL) is more common in children and acute myelogenous leukemia (AML) is more common in adults, but they are indistinguishable clinically. ALL is more often associated with infiltration of other organs, but AML can do it as well. Enlargement of the liver, spleen, and lymph nodes and bone pain are common at presentation. Disseminated intravascular coagulation (DIC) is associated with M3 promyelocytic leukemia. CNS involvement resembling meningitis is present at the time of initial diagnosis in about 5% of patients. CNS involvement is most characteristic of M4 and M5 monocytic leukemia. Rarely, a syndrome of “leukostasis” can occur when the white cell count is extremely elevated. This results from sludging of the leukemic cell in the vasculature, resulting in headache, dyspnea, confusion, and brain hemorrhage.

Diagnosis. The CBC is the first clue to the diagnosis. Most commonly, WBC is elevated, along with thrombocytopenia and anemia. In about 10% of acute leukemias, depression of all 3 cell lines is evident (aleukemic leukemia). Many other disorders can present as pancytopenia similar to leukemia such as aplastic anemia, infections involving the marrow, metastatic cancer involving the marrow, vitamin B12 deficiency, SLE, hypersplenism, and myelofibrosis. None of these will have leukemic blasts circulating in the peripheral blood, however. A bone marrow biopsy showing >20% blasts confirms the diagnosis of acute leukemia. The presence of blasts tells you the patient has acute leukemia, but blast analysis cannot be relied upon to always tell which type is present. AML is characterized by the presence of Auer rods, myeloperoxidase, and esterase. ALL is characterized by the presence of the common ALL antigen (CALLA) and terminal deoxynucleotidyl transferase (TdT). Auer rods are most specific for M3. Ultimately, the diagnosis rests upon the use of monoclonal antibodies, which recognize specific types of leukemia as well as the expression of specific CD antigens on the surfaces of the cells. Nonspe- cific findings that are also present are hyperuricemia and an increased level of LDH.


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Note

CML can be confused with a leukemoid reaction. They are distinguishable based upon the leukocyte alkaline phosphatase score.

Treatment. Chemotherapy is used initially in all patients to induce a remission. Inducing a remission means a removal of over 99.9% of the leukemic cells in the body and the elimination of peripheral blasts in circulation. This is followed by further rounds of chemotherapy to “consoli- date” the leukemia further. After chemotherapy, adults with AML or ALL should be referred for allogeneic bone marrow transplantation. The initial chemotherapy for AML is cytosine arabino- side (AraC) and either daunorubicin or idarubicin. The initial chemotherapy for ALL is dauno- rubicin, vincristine, and prednisone. Promyelocytic leukemia is managed with the addition of the vitamin A derivative all-trans-retinoic acid (ATRA). Leukostasis events are managed with leukapheresis in addition to the chemotherapy.

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ALL patients must also undergo prophylaxis of the central nervous system to prevent relapse there. The best agent for this is intrathecal methotrexate.


CHRONIC LEUKEMIA


Chronic Myelogenous Leukemia

Chronic myelogenous leukemia (CML) is a chronic myeloproliferative disorder characterized by the massive overproduction of myeloid cells. The cells retain most of their function until later in the course of the disease. Although the Philadelphia chromosome is characteristic of the disease, the cause of the production of this chromosome is unknown. It is a clonal disorder of myelocytes. The Philadelphia chromosome is a translocation between chromosomes 9 and 22, resulting in a gene producing an enzyme with tyrosine kinase activity.

Five percent of cases are Philadelphia-chromosome-negative.

Clinical Presentation. A markedly elevated white blood cell count can be found on routine blood count. The most common symptoms are fatigue, night sweats, and low-grade fever. Abdominal pain from massive enlargement of the spleen is common. Bone pain from infiltra- tion with white cells can occur. Enlarged lymph nodes are rare. Infection and bleeding are uncommon because these white cells retain the majority of their function. Rarely, a leukostasis reaction can occur from extremely elevated amounts of white cells being produced in the range of 200,000–500,000/mm3.

The white cells then clog up the vasculature, resulting in dyspnea, blurry vision, priapism, thrombosis, and stroke.

Diagnosis. The main feature of the disease is an elevated white blood cell count consisting predominantly of neutrophils with a left shift. Blasts are either absent or present in very small amounts (<5%). The leukocyte alkaline phosphatase score (LAP) is diminished. Basophilia is characteristic of CML and all myeloproliferative disorders such as polycythemia vera.

Although the B12 level is often elevated, this would not be enough to establish the diagnosis. The Philadelphia chromosome is a far more specific test for CML and should be done in a patient with a markedly elevated white cell count. A low LAP score is not as important as the PCR for Bcr/Abl. The platelet count can also be markedly elevated.

Treatment. The best initial therapy for CML is imatinib, which is also known by the manu- facturer’s name, Gleevec®. Imatinib is a direct inhibitor of the tyrosine kinase produced by the Philadelphia chromosome. There is nearly a 90% hematologic response to imatinib, and as many as 60 to 70% of patients may lose the Philadelphia chromosome. The milder the disease, the greater the degree of hematologic response. Bone marrow transplantation is no longer the



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clear first choice as therapy for CML. This is because of the extraordinary response to imatinib, as well as the high mortality associated with the bone marrow transplantation itself. If imatinib fails, then the therapy is bone marrow transplantation.


Chronic Lymphocytic Leukemia (CLL)

Chronic lymphocytic leukemia (CLL) is a massive overproduction of mature—but still leukemic— lymphocytes, usually from the monoclonal production of B lymphocytes. Etiology is unknown.

Clinical Presentation. CLL can often present as an asymptomatic elevation of white cells found on routine evaluation of patients or during investigations for other problems. Patients are exclusively older with 90% being age >50. When patients do have symptoms, they are often nonspecific—fatigue, lethargy, and uncomfortable enlargement of lymph nodes.

Infiltration of other parts of the reticuloendothelial system such as the spleen, liver, and bone marrow also occurs. Infection and bleeding are unusual presentations of the disease. Staging for CLL is as follows:

Stage 0: lymphocytosis alone

Stage 1: lymphadenopathy

Stage 2: splenomegaly

Stage 3: anemia

Stage 4: thrombocytopenia

Staging is important because the survival of untreated stage 0 and stage 1 disease is 10–12 years even without treatment. The survival of stage 3 and stage 4 disease is 1–2 years. CLL can be associated with various autoimmune phenomena such as thrombocytopenia and autoim- mune hemolytic anemia.

Diagnosis. CLL is strongly suspected when an older patient has a marked elevation in the white cell count with a marked lymphocytic predominance in the range of 80–98% lymphocytes. The marrow is often infiltrated with the leukemic lymphocytes. CD19 is an antigen strongly associated with CLL. The cell count is usually elevated in the range of 30,000–50,000, but may go as high as 150,000. “Smudge cells” seen on a smear are characteristic of CLL.

Treatment. Early stage CLL with only an elevated white cell count or enlargement of lymph nodes is not treated. However, patients with symptomatic disease always need to be treated. Those with more advanced-stage disease should receive initial therapy with fludarabine.

Fludarabine has greater efficacy than chlorambucil and should be considered the drug of choice. Autoimmune hemolysis and thrombocytopenia are treated with prednisone. Rituximab is used in those patients who express CD20, especially with autoimmune ITP or hemolytic anemias.

Hairy cell leukemia (HCL), a subtype of CLL, makes up 2% of all leukemias. It is character- ized by an accumulation of abnormal B lymphocytes. The malignant B lymphocytes (“hairy cells” ) accumulate in the bone marrow, interfering with the production of normal cells com- monly causing pancytopenia. Patients develop infections, anemia and fatigue, or easy bleed- ing. Early satiety may occur from massive splenomegaly.


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Diagnosis. Diagnose with a high hematocrit in the absence of hypoxia, carbon monoxide poisoning, or elevated erythropoietin level. The most specific test is the Janus Kinase or JAK-2.

Treatment: Phlebotomy is the primary treatment; hydroxyurea may be used in addition to or as an alternative. Aspirin is used to reduce the risk of thrombotic events.


Essential Thrombocythemia

Essential thrombocythemia is a type of platelet cancer. Platelet count may be over a million. There is either thrombosis or bleeding. The most specific test is JAK-2. Treat with hydroxyurea and sometimes anagrelide.


Clinical Recall

Which of the following treatment options could be used in the management of a patient with stage 1 CLL?

  1. Observation

  2. Fludarabine

  3. Prednisone

  4. Rituximab

  5. Fludarabine plus chlorambucil


Answer: A


PLASMA CELL DISORDERS


Multiple Myeloma

Multiple myeloma is a clonal abnormality of plasma cells resulting in their overproduction replacing the bone marrow as well as the production of large quantities of functionless immunoglobulins. The disease is characterized by various systemic manifestations such as bone, kidney, and infectious complications. Etiology is unknown.

Clinical Presentation. Bone pain is the most common clinical manifestation, usually in the back and the ribs, secondary to pathologic fractures. Radiculopathy from the compression of spinal nerve roots is also common. Infection particularly with encapsulated organisms such as Pneumococcus and Haemophilus is common. Renal failure and anemia are common. The symptoms of hypercalcemia such as polyuria, polydipsia, and altered mental status may occur. Weakness, fatigue, and pallor are common. Rarely, symptoms of a hyperviscosity syndrome such as blurry vision, confusion, and mucosal bleeding may occur.

Diagnosis. Although a normochromic, normocytic anemia is the most common laboratory finding, this is not specific for myeloma. A protein electrophoresis with a markedly elevated monoclonal immunoglobulin spike is present in almost all cases. This is most commonly IgG but may be IgA, IgD, or rarely a combination of two of these. In about 80% of individuals, routine x-ray will reveal the punched-out lytic lesion caused by the overproduction of osteoclast


Clinical Pearl Multiple myeloma causes a low anion gap.



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activating factor from the plasma cells and/or pathologic fractures at the time of diagnosis. Most commonly involved are the vertebrae, ribs, pelvic bones, and bones of the thigh and upper arm. If multiple myeloma is suspected with normal x-ray, consider MRI, CT, or PET. Serum B2

microglobulin is elevated in 75% of patients. Hypercalcemia from the destruction of bone is

common, as is an elevation in the BUN and creatinine from the damage to the kidney from the immunoglobulins, Bence-Jones protein, calcium, and hyperuricemia. A bone marrow biopsy with >10% plasma cells confirms a diagnosis of multiple myeloma. Bence-Jones protein is often not detected by a standard protein test on a urinalysis, which mainly is meant to detect albumin. A specific test for Bence-Jones protein involving acidification of the urine is required. Increased gamma globulin levels will increase the total protein and decrease the albumin level.

Treatment. Younger patients (age <70) should be treated with autologous bone marrow transplantation in an attempt to cure the disease. Older patients should receive a combination of melphalan and prednisone. Patients who are candidates for transplants should receive thalido- mide (or lenalidomide) and dexamethasone. Patients who are not candidates for transplants should receive melphalan, prednisone, and thalidomide. Hypercalcemia is treated initially with hydration and loop diuretics and then with bisphosphonates such as pamidronate.

Bortezomib is a proteasome inhibitor useful for relapsed myeloma or in combination with the other medications. It can be combined with steroids, melphalan, or lenalidomide (thalidomide).


Monoclonal Gammopathy of Uncertain Significance (MGUS)

Definition. The overproduction of a particular immunoglobulin by plasma cells without the systemic manifestations of myeloma such as bone lesions, renal failure, anemia, and hypercalcemia.

Etiology. The cause of MGUS is unknown. MGUS is a very common abnormality present in 1% of all patients age >50 and in 3% of those age >70. Some patients with MGUS may progress to multiple myeloma.

Clinical Presentation. Patients with MGUS have no symptoms. It is found on routine blood testing for other reasons.

Diagnosis. An elevated monoclonal immunoglobulin spike of serum protein electrophoresis (SPEP) in amounts lower than found in myeloma. The creatinine, calcium, and hemoglobin levels are normal. An elevated total serum protein is the clue to the diagnosis. There are no lytic bone lesions, and the bone marrow has <5% plasma cells. The beta-2 microglobulin level will be normal in most patients.

Treatment. Treatment is neither effective nor necessary.


LYMPHOMA

A 32-year-old woman comes to the office with a neck mass for the last several weeks. She also has fever, weight loss, and sweats.


Hodgkin Disease

Definition. A neoplastic transformation of lymphocytes particularly in the lymph node. It is characterized by the presence of Reed-Sternberg cells on histology which spreads in an orderly, centripetal fashion to contiguous areas of lymph nodes.


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Normal lymphocyte

National Cancer Institute


Figure 6-6. Reed-Sternberg Cell

Reed-Sternberg Cell


Etiology. Although there is a clear increase in Hodgkin disease among relatives of those with the disease, there are no clear environmental or infectious etiologies for the disorder.

Hodgkin disease has bimodal age distribution—one peak in the 20s and 60s.

Clinical Presentation. Enlarged, painless, rubbery, nonerythematous, nontender lymph nodes are the hallmark of the disease. Patients may also develop what are labeled “B” symptoms, which are drenching night sweats, 10% weight loss, and fevers. Although pruritus is common in the disease, it is not one of the “B” symptoms. Cervical, supraclavicular, and axillary lymphadenopathy are the most common initial signs of disease. Lymphadenopathy may develop anywhere in the body, however. Extralymphatic sites such as splenic involvement, skin, gastric, lung, CNS, or any other organ may possibly be involved. Extralymphatic involve- ment is more common with non-Hodgkin lymphoma.

Staging is as follows:

Stage 1: 1 lymphatic group or single extra lymphatic site

Stage 2: 2 lymphatic groups or extra lymphatic sites on same side of the diaphragm

Stage 3: Involvement of lymphatic groups on both sides of the diaphragm or involve- ment of any extralymphatic organ contiguous to the primary nodal site

Stage 4: Widespread disease with involvement of diffuse extralymphatic sites such as bone marrow or liver

The staging is the same for both Hodgkin as well as non-Hodgkin lymphoma. In Hodgkin lymphoma, staging is the single most important predictor of outcomes.

Diagnosis. An excisional lymph node biopsy is the essential first step in determining the diagno- sis. After the initial diagnosis is determined by the biopsy, the most important step is to determine the extent of disease because the stage will determine the nature of the therapy, i.e., radiation versus chemotherapy. Chest x-ray or chest CT, abdominal CT, or MRI is used to determine if the disease is localized to the supraclavicular area. Lymphangiography and laparotomy are no longer routinely used for staging. CT scan is sensitive enough to detect any involved lymph nodes. A bone marrow biopsy is used to definitively determine if the disease is truly localized.


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Adverse Prognostic Factors


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Size alone is insufficient to determine the content of some enlarged nodes. PET scan can also be used for that purpose.

Other labs tests that are often abnormal, but don’t directly alter the stage of the disease, include a CBC looking for anemia as well as increased white cell or platelet count. Eosinophilia is common. An elevated LDH level indicates an adverse prognosis. The ESR is useful prognosti- cally. Elevated liver function tests help determine the need for liver biopsy.

Treatment. Therapy is entirely based on the stage of the disease. Localized disease such as stage IA and IIA is managed predominantly with radiation. In the early stages (IA, IIA), adjunct chemotherapy may be used with radiation. All patients with evidence of “B” symptoms as well as stage III or stage IV disease are managed with chemotherapy. The most effective combination chemotherapeutic regimen for Hodgkin disease is ABVD (adriamycin [doxorubicin], bleomycin, vinblastine, and dacarbazine). ABVD is superior to MOPP (mechlorethamine, Oncovin [vincris- tine], prednisone, and procarbazine) because ABVD has fewer adverse effects such as permanent sterility, secondary cancer formation, leukemia, aplastic anemia, and peripheral neuropathy.

Hodgkin disease has several histologic subtypes. Lymphocyte-predominant has the best prognosis, and lymphocyte-depleted has the worst prognosis. The histologic subtype does not alter anything described. The lab tests, staging, and treatments are the same.



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Non-Hodgkin Lymphoma (NHL)

Definition. The neoplastic transformation of both the B and T cell lineages of lymphatic cells. NHL causes the accumulation of neoplastic cells in both the lymph nodes as well as more often diffusely in extralymphatic organs and the bloodstream. The Reed-Sternberg cell is absent.

Etiology. There are a number of infectious and autoimmune disorders associated with the develop- ment of NHL. Their absence, however, by no means excludes the presence of NHL. Infections such as HIV, hepatitis C, Epstein-Barr, HTLV-I, and Helicobacter pylori predispose to the development of NHL. HIV and Epstein-Barr are both more often associated with Burkitt lymphoma. HIV can also be associated with immunoblastic lymphoma. The main point of knowing this is that they are both high-grade lymphomas with an aggressive progression of disease.

Clinical Presentation. Enlarged, painless, rubbery, nonerythematous, nontender lymph nodes are the hallmark of the disease. Patients may also develop what are labeled “B” symptoms, which are drenching night sweats, 10% weight loss, and fevers. Although pruritus is common in the disease, it is not one of the “B” symptoms. In this sense, NHL is the same as Hodgkin disease. The differ- ence is that Hodgkin disease is localized to cervical and supraclavicular nodes 80–90% of the time, whereas NHL is localized only 10–20% of the time. NHL is far more likely to involve extralym- phatic sites as well as to have blood involvement similar to chronic lymphocytic leukemia. CNS involvement is also more common with NHL. HIV-positive patients often have CNS involvement.

The staging system for NHL is the same as that for Hodgkin disease as described.

Diagnosis. The diagnosis of NHL rests initially on an excisional lymph node biopsy. After this, the most important step is to determine the stage of the disease to determine therapy. Although this is quite similar to that described for Hodgkin disease, there are several significant differ- ences because NHL is far more likely to be widespread at initial presentation. Lymphangiogra- phy is never necessary, and staging laparotomy is rarely needed. The bone marrow biopsy is more central as an initial staging tool. Because the presence of marrow involvement means the patient has Stage IV disease and therefore needs combination chemotherapy, further invasive testing such as the laparotomy is not necessary. As with Hodgkin disease anemia, leukopenia, eosinophilia, high LDH, and high ESR often accompany the disease. PET scanning is highly sensitive and specific for nodal and extranodal sites but not for bone marrow disease.

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Treatment. As with Hodgkin disease, local disease such as stage IA and stage IIA are treated predominantly with radiation, and all those with “B” symptoms as well as stages III and IV receive combination chemotherapy. Given the frequency of more widespread disease with NHL, however, this means few NHL patients are treated with radiation alone. The initial chemotherapeutic regimen for NHL is still CHOP (cyclophosphamide, hydroxy-adriamycin, oncovin [vincristine], prednisone). More elaborate chemotherapeutic regimens for NHL, of which there are many, are beyond the scope of what is necessary to know for the Step 2 exam.

CNS lymphoma is often treated with radiation, possibly in addition to CHOP. Relapses of NHL can be controlled with autologous bone marrow transplantation. Some patients with NHL express CD20 antigen in greater amounts. When this occurs, monoclonal antibody rituximab should be used. Rituximab is an anti-CD20 antibody that has limited toxicity and adds survival benefit to the use of CHOP. Thus, R-CHOP would then become first-line therapy. Prior to using R-CHOP, always test completely for hepatitis B and C, as rituximab can cause fulminant liver injury in those with active hepatitis B or C disease.


Tumor lysis syndrome

Tumor lysis syndrome (TLS) is an oncologic emergency caused by massive tumor cell lysis, with the release of large amounts of potassium, phosphate, and uric acid into the systemic circulation. Uric acid excretion can result in the precipitation of uric acid in the renal tubules; it can also induce renal vasoconstriction, reduced renal blood flow, and inflammation, resulting in acute kidney injury. Hyperphosphatemia with calcium phosphate deposition in the renal tubules can also cause acute kidney injury.

TLS most often occurs after the initiation of cytotoxic therapy in patients with high-grade lymphoma (particularly Burkitt’s and acute lymphoblastic leukemia), though it can occur spontaneously and with other tumor types having a high proliferative rate or large tumor burden.

Patients about to receive chemotherapy for a cancer with a high cell turnover rate—especially lymphomas and leukemias—should receive prophylactic oral or IV allopurinol plus adequate IV hydration to maintain high urine output (>2.5 L/day). Rasburicase may be used as an alternative to allopurinol and is reserved for those at high-risk for developing TLS. Alkaliza- tion of the urine as a treatment of TLS is controversial.


Clinical Recall

A 25-year-old man comes to the clinic complaining of enlarged, rubbery, non-erythematous, painless, non-tender cervical lymphadenopathy. He also admits to having weight loss, fever, and night sweats. What is the best initial diagnostic step in the management of this patient?

  1. Complete blood count with erythrocyte sedimentation rate

  2. PPD or IFN-gamma release assay with CXR

  3. Upper endoscopy with gastrointestinal biopsy

  4. Excisional lymph node biopsy

  5. Abdominal CT


    Answer: D


    Note

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    Knowing each of the histologic subtypes of NHL is not necessary for the exam.


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    Clinical Pearl

    Platelet disorders can broadly be classified into 2 groups:

    PLATELET DISORDERS


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    Immune Thrombocytopenic Purpura (ITP)

    Definition. Thrombocytopenia of unknown etiology.

    Etiology. The idiopathic production of an antibody to the platelet, leading to removal of platelets from the peripheral circulation by phagocytosis by macrophages. The platelets are bound by the macrophage and brought to the spleen, leading to low platelet counts. ITP is often associated with lymphoma, CLL, HIV, and connective tissue diseases.

    Clinical Presentation. Like all platelet disorders, the patient presents initially with signs of bleeding from superficial areas of the body such as the skin, nasal and oral mucosa, GI tract, urine, and vagina. The patient is generally young, more often female, and complains of epistaxis, bruising, hematuria, dysfunctional uterine bleeding, and sometimes GI bleeding. Petechiae, purpura, and ecchymoses are often found on exam. The patient is generally otherwise healthy. Splenomegaly should be absent.

    Diagnosis. Thrombocytopenia is the major finding. A normal spleen on exam and on imaging studies such as an U/S is characteristic. Antiplatelet antibodies have a high sensitivity but poor specificity. The bone marrow should be filled with megakaryocytes indicating that there is a problem with platelet destruction and not platelet production. The bone marrow will also exclude other causes of thrombocytopenia such as primary or metastatic cancer, infiltration by infections such as tuberculosis or fungi, or decreased production problems such as drug, radiation, or chemotherapy effect on the bone marrow. The peripheral smear and creatinine should be normal, excluding other platelet destruction problems such as hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, and disseminated intravascular coagulation.

    Treatment. Prednisone is the initial therapy in almost all patients. Splenectomy is used in patients in whom very low platelet counts <10,000–20,000/mm3 continue to recur despite repeated courses of steroids. IVIG or RhoGAMTM may be used in patients with profoundly low platelet counts (<10,000 µL) or in patients at risk for life-threatening bleeding. Note that RhoGAM may only be used in Rh-positive patients. In those who recur after splenectomy, we use thrombopoietin agents romiplostim or eltrombopag. Rituximab has also been used.


    Von Willebrand Disease (vWD)

    A 22-year-old woman comes to the emergency department with epistaxis and heavy periods. She has a PT of 11 seconds (normal), a PTT of 40 seconds (prolonged), and 217,000/mm3 platelets.


    Definition. An increased predisposition to platelet-type bleeding from decreased amounts of von Willebrand factor.

    Etiology. An autosomal dominant disorder resulting in a decreased amount of von Willebrand factor. This is the most common congenital disorder of hemostasis. vWD results in a decreased ability of platelets to adhere to the endothelial lining of blood vessels. This is different from platelets aggregating with each other, which is mediated by fibrinogen. In vWD, aggregation is normal, whereas adherence is abnormal. It is not necessary to know the difference between the different subtypes of vWD for the Step 2 exam.


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    Clinical Presentation. Patients with vWD manifest platelet-type bleeding such as that described for ITP. This is mucosal and skin bleeding such as epistaxis, petechiae, bruising, and menstrual abnormalities. Both platelet problems as well as clotting factor abnormalities can result in GI and urinary tract bleeding. There is often a marked increase in bleeding after the use of aspirin.

    Diagnosis. The platelet count and appearance are normal. The bleeding time is increased particularly after the use of aspirin. The level of von Willebrand factor, also known as factor VIII antigen, is low. The ristocetin platelet aggregation test, which examines the ability of platelets to bind to an artificial endothelial surface (ristocetin), is abnormal. The PTT may be elevated in some patients because of a concomitant decrease in levels of factor VIII coagulant portion.

    Treatment. Desmopressin acetate (DDAVP) is used for mild bleeding or when the patient must undergo minor surgical procedures. It releases subendothelial stores of von Willebrand factor. Factor VIII replacement is used if desmopressin is not effective and the bleeding continues.

    Factor VIII replacement contains von Willebrand factor. This replaces the use of cryoprecipitate, which is now seldom necessary. Patients should not use aspirin. FFP is not useful.


    Check

    Bleeding Time

    Prolonged

    Check

    Platelet Count

    Check

    PTT, PT, & INR

    Hemophilia A

    (Factor 8 deficiency)

    Hemophilia B

    (Factor 9 deficiency)

    Hemophilia C

    (Factor 11 deficiency)

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    BLEEDING


    Symptoms

    Superficial Bleeding

    Deep Bleeding

    Symptoms


    Decreased Platelet Count

    Normal Platelet Count


    Causes

    Reversible Causes

    Irreversible Causes



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    Figure 6-7. Evaluation of Patients with Bleeding

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    COAGULOPATHY


    Hemophilia A and B

    Definition. The deficiency of factor VIII in hemophilia A and factor IX in hemophilia B resulting in an increased risk of bleeding.

    Etiology. Both hemophilia A and B are X-linked recessive disorders resulting in disease in males. Females are carriers of the disease. Females do not express the disease because they would have to be homozygous, which is a condition resulting in intrauterine death of the fetus. Hemophilia A is far more common than B.

    Clinical Presentation. Mild deficiencies (25% or greater activity) result in either the absence of symptoms or with symptoms only during surgical procedures or with trauma. More severe deficiency (<5–10% activity) can result in spontaneous bleeding. Factor-type bleeding is gener- ally deeper than that produced with platelet disorders. Examples of the type of bleeding found with factor deficiencies are hemarthrosis, hematoma, GI bleeding, or urinary bleeding. Bruising and central nervous system bleeding can also occur. Severe hemophilia is obvious in most patients by the age of 2. The disorder becomes apparent often at the time of circumcision.

    Diagnosis. A prolonged PTT with a normal PT is expected. A factor deficiency is strongly suspected when a 50:50 mixture of the patient’s blood is created with a normal control and the PTT drops to normal. This is known as a “mixing study.” If the PTT does not correct with mixing, then an antibody inhibitor of the factor is suspected. The mixing study will only tell you that a deficiency is present; it will not tell you which specific factor is deficient. Specific factor VIII or IX levels are necessary to determine a precise diagnosis. This is true of both hemophilia A and B.

    Treatment. Mild hemophilia can be treated with desmopressin (DDAVP). Desmopressin can also be used prior to surgical procedures in mild hemophiliacs. Desmopressin works by releasing subendothelial stores of factor VIII. More severe deficiencies are treated with replacement of the specific factor. Desmopressin does not work for hemophilia B.


    Table 6-3. Causes of Prolonged PT or PTT


    Prolonged PT

    Prolonged PTT

    Prolonged PT and PTT

    Inherited causes

    Factor VII deficiency

    vWF and factors VIII, IX, XI, or XII deficiencies

    Prothrombin, fibrinogen, factor V, factor X, or combined factor deficiencies

    Acquired causes

    PT, prothrombin time; PTT, partial thromboplastin time; vWF, von Willebrand factor.


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    Vitamin K Deficiency

    Definition. The deficiency of vitamin K resulting in decreased production of factors II, VII, IX, and X.

    Etiology. Vitamin K deficiency can be produced by dietary deficiency, malabsorption, and the use of antibiotics that kill the bacteria in the colon that produce vitamin K. The antibiotics most commonly associated are broad-spectrum drugs such as fluoroquinolones, cephalospo- rins, and other penicillin derivatives.

    Clinical Presentation. Bleeding may mimic that of hemophilia and may occur at any site. Look for oozing at venipuncture sites.

    Diagnosis. Both the PT and PTT are elevated. The PT usually elevates first and more severely. A correction of the PT and PTT in response to giving vitamin K is the most common method of confirming the diagnosis.

    Treatment. Severe bleeding is treated with infusions of fresh frozen plasma. Vitamin K is given at the same time to correct the underlying production defect.


    Liver Disease

    Definition. Coagulopathy from the decreased production of clotting factors by the liver.

    Etiology. Any severe liver disease or cirrhosis leads to a decreased production of the majority of clotting factors that are generally all made in the liver, except for factor VIII and von Willebrand factor. Factor VII is first factor to be depleted.

    Clinical Presentation. Bleeding may occur at any site, but the GI tract is the most common site.

    Diagnosis. Patients have an elevation of both the PT and PTT, but the PT elevates first and is often more severely affected. The disorder is clinically indistinguishable from vitamin K deficiency except that there is no improvement when vitamin K is given. A clear history of liver disease is often present, suggesting the diagnosis. Low platelet counts are often present from the hypersplenism that accompanies the liver disease.

    Treatment. Fresh frozen plasma is used acutely to correct severe bleeding such as melena. Long-term management is based on the nature of the liver disease.


    Disseminated Intravascular Coagulation (DIC)

    Definition. Consumptive coagulopathy from major underlying illness resulting in consump- tion of both platelet and clotting factor type and occasionally thrombosis. The bleeding is associated with a marked production of fibrin degradation products such as d-dimers.

    Etiology. Although essentially an idiopathic disorder, there is almost always a major underlying disease in the case history. Look for evidence of sepsis most commonly. Almost any disorder that results is cellular destruction and the release of tissue factor can initiate the cascade of consumption of platelets as well as clotting factors. These problems include rhabdomyolysis, adenocarcinomas, heatstroke, hemolysis from transfusion reactions, burns, head trauma, obstetrical disasters such as abruptio placenta and amniotic fluid embolism, as well as trauma, pancreatitis, and snakebites. Promyelocytic leukemia (M3) is a classic association.


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    Gram-negative sepsis causes DIC by the releasing endotoxin. In acute promyelocytic leuke- mia (M3), the destruction of leukemic granulocyte precursors results in the release of large amounts of proteolytic enzymes from their storage granules, causing microvascular damage. Other malignancies may also cause DIC by augmenting the expression of various oncogenes that result in the release of tissue factor. DIC exists in acute and chronic forms.

    HUS predominantly affects children. Most cases are caused by a shiga-like toxin produced by E. coli O157:H7 although Campylobacter, Shigella, and some viruses have also been implicated. It is one of the most common causes of acute renal failure in childhood and carries up to 10% mortality.

    HUS consists of a triad of hemolytic anemia, uremia, and thrombocytopenia. TTP has the same 3 findings, and is also associated with fever and neurologic problems. You do not have to have all 5 findings simultaneously to be considered to have TTP. The anemia in both will be intravas- cular in nature and will have an abnormal blood smear showing schistocytes, helmet cells, and fragmented red cells. LDH and reticulocyte count will be elevated and haptoglobin decreased.


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    Treatment for TTP is plasmapheresis. Plasmapheresis is used to treat severe cases of HUS but is not established in the treatment of mild disease. Mild disease resolves spontaneously. Dipyri- damole may help treat TTP by preventing platelet aggregation.

    Do not give antibiotics to those with possible HUS; if antibiotics are given, organism may release more toxins as it dies and may worsen the disease.

    Do not transfuse platelets. Even if the platelet count is low, administering platelets can actually worsen the CNS and renal abnormalities by giving more platelets as a substrate to precipitate. Small platelet plugs are actually the cause of the problem.


    Heparin-Induced Thrombocytopenia

    Heparin-induced thrombocytopenia (HIT), a complication of heparin therapy, can occur with any form of heparin. It is more common with IV unfractionated heparin than with low molecular weight (LMW) heparin.

    Type 1 HIT presents within first 2 days after exposure to heparin.

    Suspect HIT when a patient who is receiving heparin has a decreased platelet count, particularly if the drop is >50% of the baseline count, even if the platelet count nadir remains >150,000.

    Clinically, HIT is not often marked by bleeding; the most common complication is venous thromboembolism (deep venous thrombosis, pulmonary embolism), and less often, arterial thrombosis (stroke, myocardial infarction). For that reason, the disorder is sometimes called heparin-induced thrombocytopenia and thrombosis (HITT). Thrombosis develops in approximately 20% of patients with HIT, with mortality as high as 30%.

    Diagnosis of HIT is based on the combined clinical findings, thrombocytopenia characteris- tics, and lab studies of HIT antibodies (positive in ~85% of patients with type 2 HIT). Treat- ment begins with discontinuation of all heparin products (including heparin flushes of intravenous catheters), and later the administration of an alternative anticoagulant such as argatroban or lepirudin. Patients diagnosed with HIT should avoid all forms of heparin for life.


    Warfarin

    Warfarin (Coumadin) is the most widely prescribed anticoagulant for the prevention and treatment of thromboembolic disease. It was initially introduced as a pesticide against rodents, and long-acting forms of warfarin are still used for this purpose.

    Warfarin anticoagulates by inhibiting an enzyme that recycles oxidized vitamin K to its reduced form. Warfarin does not antagonize the action of vitamin K, but rather antagonizes vitamin K recycling. Once vitamin K is reduced, the vitamin K dependent factors (factors 2,7,9,10) are eventually reduced (3-5 days).

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    Despite its efficacy, treatment with warfarin has several limitations.


    Table 6-4. Recommended Management of a Supratherapeutic INR

    INR

    Bleeding Present

    Recommended Action

    <Ther to 5.0

    No

    >5.0 to

    9.0

    No

    >9.0

    No

    >20

    Any

    Life-threatening

    As per “INR >20” above

    INR: International Normalized Ratio; Ther: therapeutic INR range for the patient in question.

    *Preferred in patients at increased risk for bleeding (e.g., history of bleeding, stroke, anemia).


    Clinical Recall

    What is the most appropriate step in the management of a patient with heparin-induced thrombocytopenia and thrombosis?

    1. Continue heparin and administer warfarin

    2. Discontinue heparin and administer argatroban

    3. Discontinue the heparin substitute with warfarin

    4. Continue heparin and add lepirudin

    5. Continue heparin and monitor closely


Answer: B

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InfectioCuhsapDtiesreaTsiteles #7


Learning Objectives


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ANTIBIOTICS

Antibiotics can be grouped by their chemical class or by the type of organism they are effective against. The organisms that cause specific diseases do not change much over time. For example, MRSA, Staphylococcus aureus is still the most common cause of osteomyelitis, and Escherichia coli is still the most common cause of pyelonephritis.

What does change over time is the antibiotic that is effective against each organism and the sensitivity pattern of each organism.


Gram-Positive Cocci


Semisynthetic penicillinase-resistant penicillins

Staphylococcal and streptococcal organisms are effectively treated by medications such as the semisynthetic penicillins, including oxacillin, cloxacillin, dicloxacillin, and nafcillin. These agents are exclusively effective against Gram-positive cocci, in particular staphylococci.


Note

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Do not use vancomycin if the organism is oxacillin-sensitive.


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Note

On the exam, your answers should correspond most specifically to the organism you are treating. If you are treating a sensitive Staph aureus or Strep, answer with a specific Gram-positive drug.

Do not give an answer which provides more coverage than needed, unless there is evidence to support the presence of other organisms. If you are treating a Gram- positive infection, answer with a first-generation agent.

Methicillin belongs to this group of antibiotics as well, and was one of the original drugs developed in this class. It is not used clinically, however, because it may cause interstitial nephritis. Thus, the term “methicillin-sensitive” or “methicillin-resistant Staphylococcus aureus (MRSA)” is somewhat of a misnomer because methicillin is not actually used. When this term is used, think of the drugs oxacillin, cloxacillin, dicloxacillin, and nafcillin.

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When Staphylococcus is sensitive to the semisynthetic penicillins, and concurrent Gram-nega- tive infection is not suspected, these are the ideal agents. They are more effective than vanco- mycin when the organism is sensitive. These drugs are also sometimes referred to as “beta- lactamase-resistant penicillins” or “antistaphylococcal penicillins.” Nevertheless, the latter term is somewhat misleading because they are also effective against a number of streptococci, such as S. pneumoniae, the Viridans group, and groups A, B, C, and G Strep.


Penicillin G, penicillin VK, ampicillin, and amoxicillin

These agents are effective against streptococci, such as S. pyogenes, viridans group streptococ- ci, and S. pneumonia, but not against staphylococci.


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Chapter 7 Infectious Diseases


Macrolides, fluoroquinolones, and clindamycin

For Gram-positive infections, macrolides (erythromycin, clarithromycin, azithromycin), fluoroquinolones (levofloxacin, gemifloxacin, moxifloxacin), and clindamycin are alternatives to penicillins and cephalosporins. Macrolides should not be used for serious staph infection.

The new quinolones are very good for streptococcal infections, particularly Strep pneumoniae in the absence of outright penicillin-resistance. They are also sufficient against staph. Cipro- floxacin is a quinolone as well, but it does not cover Strep pneumoniae.


Vancomycin, linezolid, tigecycline, ceftaroline, telavancin

For Gram-positive infections, vancomycin, linezolid, and tigecycline are effective. Alterna- tives include ceftaroline, telavancin, daptomycin, and quinupristin/dalfopristin.

When there is a life-threatening penicillin-allergy or MRSA, use the agents listed above. MRSA is primarily treated with vancomycin.

Quinupristin/dalfopristin are also effective against vancomycin-resistant enterococci. Ceftaro- line is used like a third-generation cephalosporin, such as ceftriaxone, combined with a MRSA agent, such as vancomycin. Ceftaroline is the only cephalosporin to cover MRSA. These medications should not be used if the organism is sensitive to methicillin.


Gram-Negative Bacilli


Penicillins

Penicillins (piperacillin, ticarcillin, mezlocillin) are fully active against the full range of Gram- negative bacilli, such as Pseudomonas, as well as the Enterobacteriaceae. Enterobacteriaceae include E. coli, Proteus, Enterobacter, Citrobacter, Morganella, Serratia, and Klebsiella. They are only active against staph when combined with a beta-lactamase inhibitor such as piperacil- lin/tazobactam or ticarcillin/clavulanate. Ampicillin/sulbactam and amoxicillin/clavulanate will also cover staph and Gram-negative bacilli, but not Pseudomonas.

All penicillins will cover sensitive streptococci, but if the patient has only a sensitive strep, give a narrower agent, such as penicillin G or penicillin VK.


Cephalosporins

Third- and fourth-generation agents (ceftazidime; cefotaxime; ceftriaxone; cefotaxime, and cefepime) are fully active against the full range of Gram-negative bacilli, such as the Entero- bacteriaceae. Only ceftazidime and cefepime will cover Pseudomonas. Cefepime also covers staph.

Second-generation agents cover some of the Enterobacteriaceae, but not Pseudomonas. Although predominantly for use against Gram-negative organisms, ceftriaxone and cefotaxime are the best answers for penicillin-insensitive pneumococci-causing meningitis or pneumonia.


Quinolones

Quinolones (ciprofloxacin, levofloxacin, gemifloxacin, moxifloxacin, ofloxacin) cover most of the Enterobacteriaceae, such as E. coli, Proteus, Enterobacter, Haemophilius, Moraxella, Citrobacter, Morganella, Serratia, and Klebsiella. Only ciprofloxacin will reliably cover Pseudomonas.


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Daptomycin, ceftaroline, and tigecycline are drugs also effective against MRSA.


Note

Cephalosporins are safe in penicillin allergy if it is only a rash.


Clinical Pearl Ceftriaxone does not have adequate pseudomonal

coverage.


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Note

Sensitive Staph should not be treated with TMP/SMZ, doxycycline, or clindamycin.

The new fluoroquinolones (moxifloxacin, levofloxacin, and gemifloxacin) are also active against Gram-positive cocci, in particular Strep pneumoniae. They are among the first-line therapies for empiric treatment of pneumonia because they will also cover Mycoplasma, Chlamydia, and Legionella.


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Aminoglycosides and monobactams

Aminoglycosides (gentamicin, tobramycin, amikacin) and monobactams (aztreonam) have essentially the same Gram-negative coverage as listed above for the other agents. Although aminoglycosides can be synergistic with a penicillin in the treatment of staph, they are essentially exclusively Gram-negative agents. Aztreonam is exclusively a Gram-negative agent, with no strep or staph coverage at all.


Carbapenems

Carbapenems (imipenem, meropenem, ertapenem, doripenem) are fully active against Enterobacte- riaceae and Pseudomonas; they are similar in Gram-negative coverage to the aminoglycosides and third-generation cephalosporins. In addition, they have excellent staph and anaerobic coverage.

Although effective in polymicrobial infections, they are best used in Gram-negative infections.

All carbapenems are equally effective against anaerobes, as compared to metronidazole. Ertapenem will not cover Pseudomonas.


Anaerobes

The agent most active against anaerobes is metronidazole. Metronidazole has some advantages against anaerobic Gram-negative bacteria in the bowel, such as Bacteroides fragilis. Metronidazole is the first-line agent against Clostridium difficile. Clindamycin is less active against intra-abdominal anaerobes, but may have some advantages against the anaerobic streptococci found in the mouth.

The other agents with excellent anaerobic coverage virtually equal to metronidazole are the carbapenems and the beta-lactam/beta-lactamase combination medications such as piperacillin/tazobactam, ticarcillin/clavulanate, ampicillin/sulbactam, or amoxicillin/

clavulanate. The second-generation cephalosporins cefoxitin and cefotetan have fair activity against anaerobes, but they are less effective.


Skin MRSA

TMP/SMZ, clindamycin, doxycycline, and linezolid are oral agents useful for MRSA. Use these oral agents for minor MRSA infections. TMP/SMZ, clindamycin, and doxycycline cannot be used for MRSA bacteremia.


CENTRAL NERVOUS SYSTEM INFECTIONS


Meningitis

A 45-year-old man is brought to the emergency department with 1–2 days of fever, headache, nausea, and vomiting. On physical examination he is found to have neck stiffness and photophobia.


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Meningitis is an infection or inflammation of the meninges, which is the connective tissue covering the central nervous system (CNS). Most cases arise sporadically, and the precise method of spread of the microorganism into the CNS stem is not determined.

Overall, most meningitis cases are caused by viruses.


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In the past, Haemophilus influenzae was the most common cause of meningitis in children, but this has markedly decreased with

the Haemophilus type B vaccine.


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Clinical Pearl

In patients presenting with symptoms and signs of meningitis, treat empirically for bacterial meningitis while awaiting test results from the lumbar puncture.

Diagnosis. Lumbar puncture is essential for establishing the diagnosis. CT scan of the head is the best initial diagnostic test if the patient has papilledema, focal motor deficits, new onset seizures, severe abnormalities in mental status, or immunocompromised status (HIV, immu- nosuppressive medications, post-transplantation). If none of the above is present, a lumbar puncture can be safely done without doing a CT scan of the head first, which can significantly delay the diagnosis. If lumbar puncture is delayed >20–30 minutes for any reason, the best initial step is to give an empiric dose of antibiotics.

The most accurate test for bacterial meningitis on the lumbar puncture is the culture of the CSF. The results are always delayed for several days, however, and are rarely available at the time the initial therapy must be instituted. Protein levels are elevated most commonly with bacterial meningitis, but they can be elevated in any type of meningitis. Elevated protein level and/or decreased glucose level by themselves are relatively nonspecific findings. The opening pressure can be elevated with any cause of meningitis.

The Gram stain has a limited sensitivity and is positive in 50–70% of patients at most. When positive, however, the Gram stain has a high degree of specificity.

Initially, the most useful test is the cell count. Although elevated cell count by itself is nonspecific, the differential of the cells is useful. Only bacterial meningitis gives thousands of cells that are all neutrophils. A mild-to-moderate elevation in lymphocytes, with several dozen to several hundred cells, can occur with viral infection, Rickettsia, Lyme disease, tuberculosis, syphilis, or fungal (cryptococcal) etiology. Normal CSF cell count is <5 cells/mm3, which should be predominantly lymphocytes.

Specific diagnosis of nonbacterial meningitis is based on the nature of the organism. Lyme disease and RMSF are best detected with a specific immunologic response and serology. Crypto- coccus neoformans is detected initially with an India ink test and then later with an elevation in the serum and CSF cryptococcal antigen titer. Syphilis is confirmed by the presence of a positive VDRL or FTA on CSF. TB is rarely detected by AFB smear. Culture for TB has a much higher yield, particularly on several repeated LPs. PCR can also aid in the diagnosis of TB.

Treatment. Empiric therapy of bacterial meningitis in adults is best achieved with vancomycin (because of the increasing prevalence worldwide of pneumococci with decreasing sensitivity to penicillins) plus a third-generation cephalosporin such as ceftriaxone. Ampicillin is added to those with immune defects to cover Listeria and for patients age >50 or ≤1 month. You will have to recognize the risks, such as HIV, steroid use, pregnancy, or hematologic malignancies in the case description. Listeria is resistant to all forms of cephalosporins. Vancomycin is used if you know you have definite or suspected pneumococcal resistance to penicillin or if there is a chance of staphylococcal infection after neurosurgery. Lyme disease is best treated with ceftriaxone. Cryptococcus is treated initially with amphotericin. This is followed by fluconazole therapy in HIV-positive patients for life or until the patient is on HAART (highly active antiretroviral therapy) and is asymptomatic with CD4 count >100/μL for at least 3–6 months. Neurosyphilis is treated with high-dose IV penicillin. TB meningitis is treated in the same fashion as you would use for pulmonary TB (though a longer duration of 9–12 months of therapy is given). Steroid use in adult meningitis is appropriate for TB meningitis and bacterial meningitis. There is no treatment currently proven useful for viral (or aseptic) meningitis.


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Dexamethasone (corticosteroid) therapy for patients with bacterial meningitis decreases mortality and rates of deafness. The rationale for this is the inflammatory response elicited in the subarachnoid space due to bacterial cell wall lysis after antibiotics are administered; this inflammatory reaction can worsen morbidity and mortality due to bacterial meningitis.

Accordingly, dexamethasone given 15–20 minutes before or concurrently with antibiotics should produce improved outcomes (morbidity and mortality); the benefit is greatest for patients with pneumococcal meningitis. Dexamethasone should be continued for 4 days if bacterial meningitis is confirmed (positive Gram stain of CSF fluid or >1000 WBCs within the CSF can be taken as confirmation of bacterial meningitis) and discontinued if the etiology is nonbacterial (viral, fungal, etc.).


Clinical Recall

A 65-year-old man comes to the emergency department complaining of fever, stiff neck, and photophobia. Which of the following is the best empiric treatment for this patient?

  1. Vancomycin, ceftriaxone, ampicillin, and dexamethasone

  2. Nafcillin, ceftriaxone, and ampicillin

  3. Vancomycin and ceftriaxone

  4. Vancomycin, cefepime, and dexamethasone

  5. Vancomycin, ceftriaxone, and ampicillin


Answer: A


Encephalitis

A young man is brought to the emergency department by his friends because of 1–2 days of confusion and strange behavior. He had been originally complaining of a headache and fever. On the day of admission he became markedly worse and is now delirious. He is generally healthy. On physical examination you find a lethargic, confused man with an elevated temperature. You are unable to determine if he has focal neurologic findings or to obtain an accurate neurologic exam because his confusion makes him unable to follow commands.


Encephalitis is an infection of the brain, whether in the meninges or the brain parenchyma. Al- though any bacterial, protozoal, or rickettsial infection can cause encephalitis, most cases are caused by viruses, with herpes simplex (usually type I [HSV-1]) the most common.

Varicella-zoster virus, CMV, enteroviruses, Eastern and Western equine encephalitis, St. Louis encephalitis, and West Nile encephalitis are significantly less common causes.

Patients present with fever and headache but these findings are nonspecific. Altered mental status with fever and headache is the primary clue to the diagnosis. Any level of neurologic deficit may occur, ranging from slight confusion to lethargy or coma. Focal deficits of any kind can occur. Neck stiffness similar to that found in meningitis can occur, making it difficult to distinguish encephalitis from meningitis. Seizures may also occur.


Clinical Pearl Encephalitis usually presents with altered mental status,

erratic behavior, etc (brain

parenchyma involved).

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Diagnosis. Although CT or MRI of the head should be performed, it cannot give a specific diagnosis. HSV has a predilection for involvement of the temporal lobes, which can sometimes be seen on CT. Lumbar puncture is the key to the diagnosis. Formerly, a brain biopsy was necessary, but PCR (polymerase chain reaction) amplification techniques have virtually eliminated that need. PCR for HSV has a 98% sensitivity and >95% specificity, making it at least equal to the biopsy.

Treatment. HSV encephalitis is best treated with IV acyclovir. Although famciclovir and valacyclovir have activity against HSV, they are not available intravenously. Ganciclovir or foscarnet are active against CMV. Acyclovir-resistant herpes is treated with foscarnet.


Brain Abscess

An HIV-negative man is brought to the hospital because of a seizure. When he becomes more alert, you find that he has aphasia and weakness of the right hand and leg. A CT scan of the head with contrast shows enhancement of the lesion with a “ring” around the lesion.


Brain abscess is a collection of infected material within the brain parenchyma. Bacteria can spread into the brain from contiguous infections such as otitis media, sinusitis, mastoiditis, or dental infection. Organisms may also spread through the bloodstream from endocarditis or pneumonia and seed the brain. Toxoplasmosis can reactivate in those with severe HIV disease when CD4 counts are very low (<50–100/μL). Brain abscesses most commonly have Strepto- coccus in 60–70%, Bacteroides in 20–40%, Enterobacteriaceae in 25–35% and Staphylococcus in 10%, and are often polymicrobial. Because of the diversity of the organisms potentially involved, it is difficult to have a single standard therapy.

Headache is the most common symptom. Fever can be present. Focal neurologic deficits are the initial complaint in about 60% of patients. Seizures may occur, as with any form of anatom- ic abnormality of the CNS. All CNS infections can cause seizures.


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aic.cuhk.edu.hk/web8


Figure 7-1. CT Scan Demonstrating Large Cerebral Abscess

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Diagnosis. The initial test is the CT scan. Contrast is used to help identify the lesion, although CNS malignancy enhances with contrast as well. MRI is more accurate than the CT scan, although no radiologic test alone can give the precise etiology. In the case of bacterial brain abscess, examination of the abscess fluid (obtained by stereotactic aspiration or surgical excision of the abscess) for Gram stain and culture is essential. In HIV-positive patients, 90% of brain lesions will be either toxoplasmosis or lymphoma. This is the only circumstance where empiric therapy is sufficient to establish a specific diagnosis. If the lesion responds to 10–14 days of therapy with pyrimethamine and sulfadiazine, continue to administer this therapy, as it accurately predicts cerebral toxoplasmosis.

Treatment. Almost always, successful treatment requires a combination of surgical and medical management. Stereotactic aspiration (preferred) and surgical excision of the abscess are the methods used; the latter is rarely used nowadays because of significant complications.

With the exception of HIV-positive patients who are best treated with pyrimethamine and sulfadiazine, therapy should be based on the specific etiology found. One example of a combination of therapy is penicillin, metronidazole, and a third-generation cephalosporin, such as ceftazidime. Penicillin would cover the streptococci, metronidazole the anaerobes, and ceftazidime the Gram-negative bacilli.


HEAD AND NECK INFECTIONS


Otitis Media

Otitis media is an infection of the middle ear between the eustachian tube and the tympanic membrane. Viral upper respiratory infection can cause edema of the eustachian tube, which often leads to middle ear infection. The most common organisms are Strep pneumoniae (35–40%), H. influenzae (nontypeable; 25–30%), and Moraxella catarrhalis (15–20%). Viruses probably account for the rest of the cases. This is roughly the same breakdown of organism type and frequency that occurs in bronchitis and sinusitis.

Patients complain of ear pain, fever, and decreased hearing. On physical examination a red, bulging tympanic membrane is found, with loss of the light reflex. The most sensitive clinical finding is immobility of the membrane on insufflation of the ear with air. Perforation of the tympanic membrane with otorrhea occurs rarely.

Diagnosis is made through physical examination of the ear. Radiologic tests are not useful. A specific bacteriologic diagnosis can be obtained with tympanocentesis for culture, but that is rarely performed.

Treatment. Oral therapy with amoxicillin is still the best initial therapy. Amoxicillin-clavulanate is used if there has been recent amoxicillin use or if the patient does not respond to amoxicillin. Other alternatives to amoxicillin-clavulanate are second-generation cephalosporins, such as cefuroxime, loracarbef, or cefprozil, or third-generation agents, such as cefdinir or cefixime.

Patients with severe penicillin allergy should receive a macrolide such as azithromycin or clarithromycin. New fluoroquinolones such as levofloxacin, moxifloxacin, or gatifloxacin are microbiologically acceptable but are broader coverage than necessary and should not be used in children (concern for arthropathy). TMP/SMZ is sometimes used but is poorly active against Streptococcus pneumoniae.


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Sinusitis

A young woman comes to the office with several days of facial pain, a headache, cough, fever, and discolored nasal drainage. On physical examination tenderness over the maxillary sinuses and decreased transillumination of the maxillary sinuses is found.


Sinusitis is an infection of the sinuses. The most common site is the maxillary sinus, followed by ethmoid, frontal, and sphenoid sinuses.


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Wikipedia, James Heilman, MD


Figure 7-2. Sinusitis


Viruses are responsible for most cases of sinusitis. Bacterial organisms that cause sinusitis are the same ones causing otitis media.

Patients complain of facial pain, headache, postnasal drainage, and purulent nasal drainage. Headache is common and is worse when the patient leans forward. Fever occurs in about 50% of cases. Tooth pain also occurs because of the proximity of the sinuses to the teeth.

Diagnosis. Obvious cases of sinusitis do not always need radiologic confirmation prior to treatment. Sinus x-rays are of little value, and routine imaging as a rule is not recommended. If imaging is required because of concern for complications, uncertain diagnosis, or lack of response to treatment, CT scan of the sinuses is the test of choice since it provides greater detail. Occasionally, sinus puncture is necessary to confirm a specific bacteriologic etiology, particularly when the patient does not respond to therapy or if there are frequent recurrences.


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Treatment. Mild or acute uncomplicated sinusitis can be managed with decongestants, such as oral pseudoephedrine or oxymetazoline sprays. More severe pain with discolored nasal discharge is treated with antibiotics. The drugs used are in the same order and type as those listed above for otitis media because the microbiology is almost identical.

Most cases of viral rhinosinusitis resolve in 7–10 days with symptomatic management (antihis- tamines, NSAIDS, and decongestants). If symptoms persist beyond that point or get worse, antibiotics should be considered.


Pharyngitis

Pharyngitis is irritation or inflammation of the back of the throat (or the pharynx). Although most pharyngeal infections are caused by viruses, the most important cause is group A

beta-hemolytic streptococci (S. pyogenes). This is because of the possibility of the organism progressing on to rheumatic fever or glomerulonephritis. S. pyogenes only accounts for 15–20% of cases of pharyngitis.

Sore throat with cervical adenopathy and inflammation of the pharynx with an exudative covering is highly suggestive of S. pyogenes. Most viruses do not give an exudate, although the Epstein-Barr virus can. Mild S. pyogenes infections may not give an exudate, and this is one of the reasons diagnostic testing is useful. Hoarseness and cough are not suggestive of pharyngitis.


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Figure 7-3. Strep Throat


Diagnosis. The rapid streptococcal antigen test is 80% sensitive but >95% specific. A positive test can be considered the equivalent of a positive culture, whereas a negative test should be confirmed with a culture.

Treatment. Penicillin remains the mainstay of therapy. Macrolides and oral, second- generation cephalosporins are alternatives in the penicillin-allergic patient.


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Note

Flu vaccine is indicated annually for everyone age >6 months.

Influenza

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Influenza is a systemic viral illness from influenza A or B, usually occurring in an epidemic pattern and transmitted by droplet nuclei. Influenza can lead to damage to the respiratory epithelium, leading to sinusitis, otitis media, bronchitis, and pneumonia.

Patients present with a systemic illness characterized by fever, myalgias, headache, and fatigue. Upper respiratory symptoms tend to predominate. These include runny nose (coryza), nonproductive cough, sore throat, and conjunctival injection.

Diagnosis is initially confirmed with rapid antigen detection methods of swabs or washings of nasopharyngeal secretions. Viral culture is the most accurate test but is usually not available rapidly enough to make it useful in acute patient management.

Treatment. Symptomatic therapy with acetaminophen and antitussives is useful. Specific antiviral medications for both influenza A and B are the neuraminidase inhibitors oseltamivir and zanamivir. They should be used within 48 hours of the onset of symptoms to limit the duration of symptoms. Amantadine and rimantadine should not be used in the empiric therapy of influenza. Influenza vaccine is recommended annually in the general public.

The most important candidates for vaccination are those with chronic lung and cardiac disease, pregnant women in any trimester, residents of chronic care facilities, health-care work- ers, immunosuppressed patients, and those with diabetes and renal dysfunction. Influenza vaccine is contraindicated in those who are highly allergic to eggs and which would result in anaphylaxis.


Clinical Recall

An elderly, HIV-positive man comes to the emergency department complaining of fever, headache, and muscle weakness. He is subsequently diagnosed with a brain abscess by imaging studies. Which of the following is the most appropriate next step in management?

  1. Brain biopsy to confirm pathogen

  2. Ceftriaxone, vancomycin, ampicillin and steroids

  3. 10–14 days of therapy with pyrimethamine and sulfadiazine

  4. HSV PCR followed by IV acyclovir

  5. LP with culture of CSF fluid


Answer: C



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LUNG INFECTIONS


Bronchitis

A 63-year-old man comes to the office with a cough productive of yellowish sputum for the last several days. He has smoked 1 pack of cigarettes a day for the last 30 years. On physical examination the lungs are clear and temperature is 38.3 C (101 F). Chest x-ray is normal.


Bronchitis is an infection of the lung, limited to the bronchial tree with limited involvement of the lung parenchyma. Acute exacerbations of chronic bronchitis (COPD) are often difficult to distinguish from a pneumonia until chest x-ray is performed.

Acute bronchitis is an acute inflammation of the tracheobronchial tube. The vast majority of cases are caused by viruses. S. pneumoniae and H. influenzae have not been implicated. A small percentage of nonviral cases are due to M. pneumoniae, C. pneumoniae, and B. pertussis.

The most common organisms responsible for chronic bronchitis are similar to those causing sinusitis and otitis media (Streptococcus pneumoniae, nontypeable Haemophilus influenzae, and Moraxella). Viruses account for a significant percentage but are often not confirmed. Cigarette smoking is the most common causative factor; even 1 cigarette per day is enough to paralyze the cilia, which clear the bronchial tree of mucus and inhaled impurities, for 24 hours.

Patients present with a cough often accompanied by sputum production. A bacterial etiology is suggested by discolored sputum, but it is impossible to determine the specific bacterial etiology by sputum characteristics alone. Although the lung exam may reveal rales, patients most commonly have clear lungs. Signs of consolidation, such as increased fremitus, are absent.

Low-grade fever may be present, but patients are most commonly afebrile.

Diagnosis. Signs of respiratory infection, such as cough and sputum, with a normal chest x-ray confirm the diagnosis.

Treatment. Mild acute cases often do not require therapy because they are often caused by viruses that resolve spontaneously. Acute exacerbations of chronic bronchitis can be treated with amoxicil- lin, doxycycline, or TMP/SMZ, if there has not been recent antibiotic use. Repeated infection or patients not responding to amoxicillin should be treated with any of the following: amoxicillin/ clavulanate, clarithromycin, azithromycin, oral second- or third-generation cephalosporins, or the new fluoroquinolones, gemifloxacin, levofloxacin, or moxifloxacin.


Lung Abscess

A 58-year-old alcoholic man was admitted last night for several weeks of cough, sputum, and fever. He has lost 15 pounds and is feeling weak. On initial examination he is febrile and appears thin. He has very poor dentition. The lung examination is normal. The patient also exhibits a foul odor on the oral examination.


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Note

Pneumonia is the only cause of death from an infectious disease in the top 10 causes of death in the United States.

Lung abscess is necrosis of the pulmonary parenchyma caused by microbial infection.

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Diagnosis. Sputum for Gram stain and culture will not be able to show the causative anaerobic organism in a lung abscess. Chest x-ray in an abscess will often show a thick-walled cavitary lesion. Chest CT can help define the exact extent of the cavity. In the upright position the lower lobes are the most common sites of aspiration. In the supine position the posterior segment of the right upper lobe is the most common site. Aspiration of the abscess fluid is necessary for a specific bacteriologic diagnosis.

Treatment. In the absence of specific microbiologic diagnosis, clindamycin is good empiric coverage for the “above the diaphragm” anaerobes most often found. Penicillin is also acceptable.

In contrast to most abscesses where drainage is the rule, lung abscesses rarely require drainage in the antibiotic era. Most respond to antimicrobial therapy and drain spontaneously by communicating with larger bronchi. Therefore, the answer to the question, what is the best initial therapy for a lung abscess, is antibiotics such as clindamycin, not drainage.


Pneumonia

Pneumonia is an infection of the lung parenchyma. It is the 6th leading cause of death in the United States. It is not necessary to have a particular predisposing condition, although some conditions do predispose to having pneumonia: cigarette smoking, diabetes, alcoholism, malnutrition, obstruction of the bronchi from tumors, and immunosuppression in general. Neutropenia and steroid use predispose to Aspergillus infection.

The most common cause of community-acquired pneumonia in all groups is S. pneumoniae when an actual cause is identified (however, viruses are the most common cause in children age <5). Subsequent causes may vary, but S. pneumoniae is always number one. Hospital- acquired or ventilator-associated pneumonia shows a predominance of Gram-negative bacilli such as E. coli, the other Enterobacteriaceae, or Pseudomonas, as well as MRSA.


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Table 7-1. Frequency of Infectious Agents Causing Pneumonia

“Typical”

40–60%

Strep pneumoniae

15–35%

Haemophilus

2–10%

Moraxella

<5%

“Atypical”

10–30%

Legionella

0–15%

Mycoplasma

10%

Chlamydia

5–10%

Viral

2–20%

Unknown

30–60%


Specific predispositions are as follows:


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Patients with pneumonia present with cough, fever, and often sputum production. Severe pneumonia of any cause may present with dyspnea. The quality and degree of sputum pro- duced might provide useful clues to the microbiologic etiology of pneumonia at the initial pre- sentation. Bacterial infections such as S. pneumoniae, Haemophilus, and Klebsiella have signifi- cant purulent sputum production because they are infections of the alveolar air space.

Diagnosis. The most important initial test for any type of pneumonia is the chest x-ray. Besides being able to simply show the presence of disease, the chest x-ray gives the initial clue to determining the diagnosis. The most important initial clue to the diagnosis is whether the infiltrates are localized to a single lobe of the lung or whether they are bilateral and interstitial.

S. pneumoniae (and other causes of “typical” pneumonia) usually appear as a lobar pneumonia with parapneumonic pleural effusion. Interstitial infiltrates are associated with PCP, viral, Mycoplasma, Chlamydia, Coxiella, and sometimes Legionella pneumoniae. Sputum should be obtained for both Gram stain as well as culture. Sputum culture is the most specific diagnostic test for lobar pneumonia, such as with S. pneumoniae, Staphylococcus, Klebsiella, and Haemophilus. The other organisms (viral, Mycoplasma, Chlamydia, Coxiella, etc.), the so-called “atypical” organisms, will not show up on a Gram stain or regular bacterial culture for various reasons. Occasionally, more invasive tests are necessary to confirm the diagnosis such as


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bronchoscopy, thoracentesis, pleural biopsy, or culture of pleural fluid. Ultimately, the most specific diagnostic test for pneumonia is with an open lung biopsy.

Organism-specific diagnostic methods are as follows:

Treatment. Treatment depends on whether the patient has a mild disease that can be treated as an outpatient or a more severe illness that must be treated with IV antibiotics as a hospital- ized inpatient. The major determinants of severity are the degree of hypoxia, such as a Po2 <60

mm Hg, oxygen saturation <94% on room air, or a respiratory rate >30/min; confusion or

disorientation; uremia; and hypotension (systolic BP <90 mm Hg and diastolic BP <60 mm Hg). Other markers of severity are high fever, hypothermia, leukopenia (WBC <4,000/mm3), rapid pulse (>125/min), hyponatremia, or dehydration as determined by an elevated BUN. Patients with serious underlying diseases such as cancer, liver disease, renal disease, or chronic lung disease often do better in hospital with IV medications.

The specific organism causing pneumonia is rarely, if ever, known at the time that the initial therapeutic decision must be made. Empiric therapy for pneumonia managed as an outpatient is with a macrolide, such as azithromycin or clarithromycin. This is because of the high frequency of Mycoplasma and Chlamydia pneumoniae as the cause of less severe community-acquired pneumo- nia (CAP). New fluoroquinolones (levofloxacin, moxifloxacin, or gemifloxacin) are alternatives.

Although oral second- and third-generation cephalosporins and amoxicillin/clavulanate are often used, they do not cover the atypical pathogens well.

Hospitalized patients with CAP should receive either levofloxacin, moxifloxacin, or gatifloxacin or a second- or third-generation cephalosporin such as cefotaxime or ceftriaxone combined with a macrolide antibiotic such as azithromycin or clarithromycin (or doxycy- cline).


Table 7-2. Empiric Therapy of Community-Acquired Pneumonia


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CURB-65 indicates need for hospitalization in pneumonia:

Confusion Uremia

Respiratory distress Blood pressure low Age >65


Outpatient (Nonhospitalized)

Inpatient (Hospitalized)

First choice: macrolides:

Azithromycin, clarithromycin

Alternatives: new fluoroquinolones:

Levofloxacin, moxifloxacin, gemifloxacin

New fluoroquinolones (levofloxacin, moxifloxacin, or gemifloxacin)

or

Second- or third-generation cephalosporins (cefuroxime or ceftriaxone) combined with a macrolide or doxycycline

or

Beta-lactam/beta-lactamase combination drug (ampicillin/sulbactam; ticarcillin/ clavulanate; piperacillin/tazobactam) combined with doxycycline or a macrolide



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Treatment of Hospital-Acquired Pneumonia. Those patients who develop pneumonia after 5–7 days in the hospital are at increased risk of infection from drug-resistant, Gram-negative bacilli (Pseudomonas, Klebsiella, E. coli, etc.) or gram-positive bacilli such as

methicillin-resistant Staphylococcus aureus (MRSA). Empiric therapy of hospital-acquired pneumonia is with third-generation cephalosporins with antipseudomonal activity (such as ceftazidime) or carbapenems (such as imipenem) or with beta-lactam/beta-lactamase inhibitor combinations (such as piperacillin/tazobactam) and coverage for MRSA with vancomycin or linezolid. Aminoglycosides (gentamicin, tobramycin, amikacin) are often added to empiric gram-negative coverage for synergy and to ensure that the patient might be getting at least one drug if the bacteria is multidrug resistant. Antibiotic therapy can then be adjusted when results of cultures (sputum, blood, bronchoalveolar lavage, and/or pleural) become available.

Treatment of specific organisms is as follows:


Pneumococcal vaccine

Those patients at increased risk for pneumonia should receive pneumococcal vaccine. Those who should receive the vaccine include all patients age >65, as well as those with any serious underlying lung, cardiac, liver, or renal disease. Immunocompromised patients, such as those on steroids, HIV-positive persons, splenectomized patients, diabetics, and those with leukemia or lymphoma, should be vaccinated at the earliest possible opportunity. The vaccine is 60–70% effective. Re-dosing in 5 years is only necessary for those with severe immunocompromise or in those who were originally vaccinated before the age of 65. In generally healthy persons vaccinated age >65, a single dose of vaccine is enough to confer lifelong immunity.


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Tuberculosis

A 37-year-old resident of a maximum-security correctional facility has been having a cough, voluminous sputum production, and fever for the last few weeks. He has had a 10-pound weight loss and feels very weak.


Tuberculosis (TB) is an infection with Mycobacterium tuberculosis. Worldwide, TB is one of the top 3 causes of all deaths.

TB is spread exclusively by person-to-person transmission by means of respiratory droplet infection. There is no animal reservoir of the disease. Bacillus Calmette-Guérin (BCG) vaccination is used in many parts of the world outside the United States to try to prevent infection. It is, at best, 50% effective and is never indicated for routine use in the United States.

Besides immigrants, TB occurs predominantly in persons with specific risk for exposure, such as alcoholics, healthcare workers, prisoners, homeless shelter residents, nursing home residents, and chronically debilitated patients whose weakened immune systems allow for more frequent re-activation of latent infection. Impairment of T-cell–mediated cellular immunity is the most significant defect associated with re-activation. This is why steroid use, organ transplantation, leukemia, lymphoma, and HIV are such important risk factors.


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Centers for Disease Control and Prevention


Figure 7-4. Tuberculosis X-ray


Patients present with cough, sputum, fever, and an abnormal lung exam. They may be impossible to distinguish clinically from those with pneumonia.


Note

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Nearly 25% of the world’s population has been exposed to TB and would be reactive to PPD testing. Until the middle of this century, TB was the most common cause of death in the United States, but it is now at an all-time low, with

<15,000 cases per year (over half of those are recent immigrants).


Note

Lymph node involvement (adenitis) is the most frequently involved extrapulmonary site in TB.


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Clinical Pearl

Newer tests may provide TB sensitivity testing in a few weeks, thus the period of using 4 drugs is significantly shortened.

Do not use PPD testing to diagnose acute cases of TB. PPD is relatively insensitive and nonspecific particularly with acute illness.

Treatment. Initial therapy of TB before the results of sensitivity testing are known consists of 4-drug therapy with isoniazid (INH), rifampin (Rif), pyrazinamide (PZA), and ethambutol (ETB). All 4 drugs are continued for the first 2 months or until sensitivity testing is known. PZA and ETB are then discontinued, and therapy continues with INH and rifampin for another 4 months. This makes routine therapy last for a total of 6 months. The fourth drug, ETB, is given if the sensitivity is not known. The only forms of TB that definitely must be treated for longer than 6 months are TB meningitis (12 months), TB in pregnancy (9 months), and osteomyelitis. HIV-positive persons may be treated for 6–9 months, but there is no clear evidence that 9 months is necessary, i.e., even in HIV-positive persons, 6 months of therapy is effective. INH use should generally be combined with vitamin B6 (pyridoxine) to prevent peripheral neuropathy that can be a side effect of INH.

Pregnant patients should not receive PZA or streptomycin. Steroid use with TB medications is only your answer for TB meningitis and TB pericarditis.

All of the TB medications can cause liver toxicity, except streptomycin. INH also causes peripheral neuropathy because of pyridoxine deficiency. Rifampin is associated with causing a benign change in the color of all bodily fluids to orange/red. This color is dangerous only because it could stain contact lenses and white underwear. Ethambutol is associated with optic neuritis, which can cause color blindness and other visual disturbances. PZA can cause a benign hyperuricemia. Don’t treat the hyperuricemia unless there are symptoms of gout associated with it, which rarely occurs.


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Diagnosis and Treatment of Latent TB Infection. The PPD test and interferon gamma release assay (IGRA) are used to screen asymptomatic populations at risk of TB to see if they have been exposed and are at increased risk of re-activating the disease. The AFB stain and culture of the affected tissues should be performed. PPD is considered positive based on the amount of induration of the skin 48–72 h after the intradermal (not subcutaneous) injection of the PPD. Erythema is irrelevant. A positive PPD or IGRA roughly indicates a 10% lifetime risk of develop- ing TB in HIV-negative persons. Most of the active cases will develop within the first 2 years after converting to a positive test. HIV-positive persons have a roughly 7–10% risk per year of developing active disease. Previous BCG vaccination does not alter these recommendations. The cutoffs are as follows:

5 mm:

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V. vulnificus (associated with ingestion of raw shellfish); causes severe disease in those with underlying liver disease; also associated with iron overload and the development of bullous skin lesions

Although it is important to be familiar with these associations, remember that virtually any food can be contaminated by almost any organism. The most important thing is not what food you eat but whose dirty hands touched your food and what were they contaminated with.

Clinical Presentation. The most important feature of any person presenting with possible food poisoning is the presence or absence of blood in the stool. Blood is most commonly associated with invasive enteric pathogens, such as Salmonella, Shigella, Yersinia, invasive

  1. coli, and Campylobacter. The time between the development of the diarrhea from the ingestion of the food is not as important as the presence of blood. Incubation times are helpful only if you have a group outbreak and you can pinpoint a common source of contamination. In other words, the last thing you eat is not necessarily the thing that was contaminated. The invasive enteric pathogen may be causing infection in the absence of blood, however, and the absence of blood does not exclude them. Campylobacter is rarely associated with Guillain-Barré syndrome.

    Ingestion of ciguatera toxin causes symptoms within 2–6 hours, which includes paresthesias, numbness, nausea, vomiting, and abdominal cramps. In severe cases symptoms can be neurologic (weakness, reversal of hot-cold sensations), and cardiovascular (hypotension).

    Neurologic symptoms can be severe, progressive, and debilitating.

    There is no specific therapy to reverse ciguatera poisoning. The most commonly implicated fish are barracuda, red snapper, and grouper.

Scombroid is a type of poisoning that occurs after ingestion of scombroid fish (tuna, mackerel, mahi mahi), which may contain a lot of histamine. When ingested, scombroid can give symptoms within a few minutes: rash, diarrhea, vomiting, and wheezing, along with a burning sensation in the mouth, dizziness, and paresthesias.

Diagnosis. When there is no blood present in the stool, determine the etiology of the diarrhea via a stool test for the presence of WBCs with methylene blue testing. WBCs will indicate that there is an invasive pathogen, but only a culture will identify the specific type.


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Giardia and Cryptosporidia are detected by direct examination of the stool for the parasites, as well as for their eggs. A special modified AFB stain is necessary to detect Cryptosporidia. Stool ELISA is also used for Giardia.

Treatment. Therapy is determined by the severity of disease. Mild infections with the invasive pathogens and viruses usually require only oral fluid and electrolyte replacement. More severe infections, such as those producing high fever, abdominal pain, tachycardia, and hypotension, require IV fluids and oral antibiotics.

You rarely, if ever, have the luxury of knowing the specific etiology when the initial therapeutic decision must be made. The best initial empiric antibiotic therapy of an invasive pathogen is a fluoroquinolone, e.g., ciprofloxacin.

Organism-specific therapy is as follows:

All forms can occasionally present with fulminant hepatic necrosis and acute liver failure.

The most common presentation of acute hepatitis of any cause is jaundice, dark urine, light- colored stool, fatigue, malaise, weight loss, and a tender liver. On physical examination the liver may be enlarged.


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You cannot distinguish the precise viral etiology of the hepatitis by initial presentation alone. In fact, drug-induced hepatitis, i.e., that from isoniazid or massive alcohol use, may present with the same symptoms. Hepatitis B and C can also produce symptoms similar to serum sickness, such as joint pain, rash, vasculitis, and glomerulonephritis. They also lead to cryo- globulinemia. Hepatitis B has been associated with the development of polyarteritis nodosa (PAN). Hepatitis E has been associated with a more severe presentation in pregnant women.


Table 7-3. Comparative Features: Hepatitis A, B, C, E, and Delta

Feature

Hepatitis A

Hepatitis B

Hepatitis C

Delta

Hepatitis E

Incubation period (wk)

2–6 (avg. 4)

4–26 (avg. 13)

2–20

4–8

Transmission

Fecal-oral

Sexual >

parenteral

Parenteral > sexu- al

Parenteral, sexual

Fecal-oral

Severity

Mild

Occasionally severe

Usually

subclinical

Co-infection with B

Mild, except in pregnant women

Fulminant hepatitis

Rare

Very rare (1% of icteric patients

Extremely rare

Co-infection occasional

Rare

Symptoms

Fever, malaise, headache, anorexia, vomiting, dark urine, jaundice

As with A, but 10–20% with serum sickness-like

(joint pain, rash)

Only 20% acutely symptomatic

As with A

As with A

Carrier state

None

Yes

Yes

Yes

None

Chronicity (%)

0

5–10

80

5

0

Associated with blood

transfusion (%)

Very rare

5–10

Almost negligible 2% to routine screening

Occurs, but frequency unknown

Rare

Serology

Anti-HAV IgM fraction IgG fraction

HBsAg, HBsAb HBeAg

Anti-HBs Anti-HBc

Anti-HBe

Antibody to hepatitis C

PCR-RNA

Anti-delta IgM fraction IgG fraction

Anti-Hep E IgM

IgG

Postexposure prophylaxis

Immunoglobin Hep A vaccine

HBIg/Hep B vaccine

None effective

None

Unknown

Association with cirrhosis

No

Yes

Yes

Yes

No

Association with primary

hepatocellular carcinoma

No

Yes

Yes

Yes

No



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Note

For the treatment of

hepatitis B, entecavir, adefovir, tenofovir, and telbivudine can be used in place of lamivudine.

Diagnosis. All forms of viral and drug-induced hepatitis will produce elevated total and direct bilirubin levels.

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There are a number of approved therapies to treat HCV, such as sofosbuvir/ledipasvir, simepre- vir, sofosbuvir, and Viekira Pak (ombitasvir, paritaprevir and ritonavir tablets co-packaged with dasabuvir tablets that may be prescribed with or without ribavirin). Simeprevir and sofosbuvir can be prescribed together with or without ribavirin, or each may be separately combined with ribavirin and in some cases peginterferon as well.


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Sofosbuvir/ledipasvir, the current preferred HCV treatment, is 2 drugs formulated in to one daily pill. For genotype 1 success rates of sofosbuvir/ledipasvir are around 94–99%, while treatment duration is 8–12 weeks. Both are direct-acting antivirals (DAAs) which means they directly interfere with hepatitis C virus replication. Sofosbuvir is a polymerase inhibitor while ledipasvir, an NS5A inhibitor. Patients who have never been treated for HCV—whether they have cirrhosis or not—take sofosbuvir/ledipasvir for 12 weeks. Treatment-naïve patients without cirrhosis whose pre-treatment viral load (HCV RNA) is <6 million IU/mL may be considered for 8 weeks of treatment.

When hepatitis C treatment is working, the virus will become undetectable within 4–12 weeks and will remain that way throughout treatment. Patients are considered cured when they have achieved what is known as a sustained virologic response (SVR), or continuation of this undetectable status, 12–24 weeks after completing therapy.

After a needlestick from a hepatitis B surface-antigen—positive patient, the person stuck should receive hepatitis B immunoglobulin (HBIg) and hepatitis B vaccine. If the person stuck already has protective levels of surface antibody to hepatitis B present in the blood, then no further therapy is indicated. There is no effective postexposure prophylaxis to hepatitis C, and there is no vaccine. All healthcare workers, IV drug users, and others at risk should be vaccinated for hepatitis B. All newborn children are vaccinated against hepatitis B and A. Hepatitis A vaccine should be given to those traveling to countries that may have contaminated food and water, those with chronic liver disease, and those with high risk sexual behavior.


Clinical Recall

Which of the following Hepatitis B markers indicates a high level of infectivity?

  1. HBsAg

  2. HBeAg

  3. HBcAg

  4. HBcAg IgM

  5. HBcAg IgG


Answer: B


GENITAL AND SEXUALLY TRANSMITTED INFECTIONS


Urethritis

A 31-year-old man is in your clinic today with several days of urinary frequency, urgency, and burning.


Urethritis is inflammation of the urethra.

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Patients present with purulent urethral discharge; dysuria, urgency, and frequency in urination.

Smear can show the Gram-negative, coffee bean–shaped diplococci intracellularly. Serology (fluorescent antibodies) for chlamydia by swabbing the urethra, or by ligase chain reaction test of voided urine. Culture for gonorrhea is the most specific test for gonorrhea.

Treatment. Single-dose ceftriaxone intramusculary and single-dose azithromycin orally is now the treatment of choice. An alternative regimen with doxycycline for 7 days can also be used. Gonorrhea can also be treated with single-dose cefixime. This is the same treatment as that for cervicitis. Ciprofloxacin should not be used as first-line therapy for gonorrhea.


Pelvic Inflammatory Disease

Pelvic inflammatory disease (PID) describes a group of infections involving the fallopian tubes, uterus, ovaries, or ligaments of the uterus. The etiology is N. gonorrhoeae, Chlamydia, Mycoplasma, anaerobic bacteria, or Gram-negative bacteria. Intrauterine devices predispose to PID.

Clinical findings include lower abdominal and pelvic pain on palpation of the cervix, uterus, or adnexa; fever, leukocytosis, and discharge are common. Cervical motion tenderness is key. Discharge from the cervix may be present.

To diagnose, do culture on Thayer-Martin for gonococcus and Gram stain of discharge, increased ESR.

Treatment. Doxycycline and cefoxitin (or cefotetan) for inpatient therapy. Outpatient therapy is with single-dose ceftriaxone intramuscularly and doxycycline orally for 2 weeks. The main reason to treat in hospital is a high WBC or high fever. Outpatient therapy can also be with 2 weeks of oral ofloxacin and metronidazole as a second-line agent.

Complications of PID include infertility and ectopic pregnancy.


Syphilis

A 43-year-old man comes to the clinic with several days of an ulcerated genital lesion. He also has some surrounding adenopathy.


Syphilis is a systemic contagious disease caused by a spirochete; characterized by periods of active manifestations and by periods of symptomless latency. It is caused by Treponema pallidum.

Syphilis can be classified as being congenital or acquired.


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Congenital


Note

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Use the FTA to exclude neurosyphilis in CSF.


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Figure 7-6. Syphilis, Secondary Palms


Diagnosis. Screening tests are the VDRL and RPR; specific tests are the FTA-ABS, MHA-TP, and Darkfield exam of chancre. There can be false–positives VDRL with EBV, collagen vascular disease, TB, and subacute bacterial endocarditis.

Treatment. Penicillin is the drug of choice for all stages of syphilis. A reaction called Jarisch- Herxheimer can occur in >50% of patients (general malaise, fever, headache, sweating rigors, and temporary exacerbations of the syphilitic lesions 6–12 hours after initial treatment).


Chancroid

Chancroid is an acute, localized, contagious disease characterized by painful genital ulcers and suppuration of the inguinal lymph nodes. It is caused by Haemophilus ducreyi (Gram-negative bacillus).


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Figure 7-7. Chancroid Lesion


Patients present with small, soft, painful papules that become shallow ulcers with ragged edges. They vary in size and coalesce. Inguinal lymph nodes become very tender and enlarged.

Diagnosis is made on clinical findings; do a Gram stain initially with culture to confirm. PCR testing is useful. Treatment is azithromycin single dose or ceftriaxone intramuscularly (single dose). Alternatives include erythromycin for 7 days or ciprofloxacin for 3 days.


Lymphogranuloma Venereum

Lymphogranuloma venereum is a contagious, sexually transmitted disease having a transitory primary lesion followed by suppurative lymphangitis. It is caused by Chlamydia trachomatis.

Clinical findings include the following:

Diagnosis is made by clinical examination, history, and a high or rising titer of complement fixing antibodies. Isolate chlamydia from pus in buboes. Treat with doxycycline or erythromycin.


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Figure 7-8. Lymphogranuloma Venereum


Granuloma Inguinale

Granuloma inguinale is a chronic granulomatous condition, probably spread by sexual contact. It is caused by Donovania granulomatis Calymmatobacterium granulomatis.

A painless, red nodule will develop into an elevated granulomatous mass. In men, it is seen on the penis, scrotum, groin, and thighs. (In homosexual men, the anus and buttocks are com- mon areas.) In women it is found on the vulva, vagina, and perineum.

Healing is slow, and there is scar formation. It looks like condyloma lata or carcinoma.

Diagnosis is made clinically and by performing a Giemsa or Wright stain (Donovan bodies) or smear of lesion. Also do punch biopsy. Treat with doxycycline, ceftriaxone, or TMP/SMZ. Erythromycin is an alternative.


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Figure 7-9. Lesions of Granuloma Inguinale Due to

Calymmatobacterium Granulomatis Infection


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Genital Herpes

Genital herpes is generally the herpes virus type II, although type I may be seen. Vesicles develop on the skin or mucous membranes; they become eroded and painful and present with circular ulcers with a red areola. Itching and soreness usually precede them. Lesions are commonly seen on the penis (men) and on the labia, clitoris, perineum, vagina, and cervix (women).

The ulcers are scarring and there can be inguinal lymphadenopathy.

Diagnosis is made with the Tzanck test and culture. Treat with oral acyclovir, famciclovir, or valacyclovir. Make sure to educate the patient about the relapsing nature of the disease. Those with frequent recurrence should be given chronic suppressive therapy.


Genital Warts

Genital warts are also known as condylomata acuminata or venereal warts. They are caused by the papilloma virus.

Genital warts are commonly found on warm, moist surfaces in the genital areas. They appear as soft, moist, minute, pink, or red swellings which grow rapidly and become pedunculated. Their cauliflower appearance makes them unique in appearance.

Diagnosis is made by clinical appearance. Differentiation must be made between flat warts and condylomata lata of secondary syphilis. Treatment includes the following:


Clinical Recall

Which of the following is the treatment of choice for tertiary syphilis?

  1. IM penicillin G x 1 dose

  2. PO doxycycline x 14 days

  3. IV penicillin G x 10 days

  4. Doxycycline x 28 days

  5. IV ceftriaxone x 1 day


Answer: C

Clinical Correlate Transmission of genital herpes commonly occurs during an

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asymptomatic phase, when a

person who is shedding the virus inoculates virus onto a mucosal surface of the sexual partner.


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URINARY TRACT INFECTIONS


Cystitis

A 32-year-old woman is in your office because of dysuria. For the last several days, she has burning on urination with increased frequency and urgency to urinate.


Cystitis is infection of the urinary bladder. It is very common, mostly in women. In the United States, it causes 6 million office visits each year.

Etiology.



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Acute Bacterial Pyelonephritis

Acute bacterial pyelonephritis is an acute patchy, most often unilateral, pyogenic infection of the kidney. Infection usually occurs by ascension after entering the urethral meatus.


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Note

Injection drug use is a significant risk factor for vertebral osteomyelitis in adults.


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Presentation. Pain, erythema, swelling, and tenderness over the infected bone. With vascular insufficiency, there is often an obvious overlying or nearby ulceration or wound. Occasionally, a draining sinus tract is present.

Diagnosis. The earliest tests to detect osteomyelitis are the technetium bone scan and the MRI. Both have equal sensitivity for early pick-up, but the MRI can allow better differentiation between the overlying soft-tissue infection and bone. The MRI can be less readily available, however.

Treatment. Acute hematogenous osteomyelitis in children can usually be treated with antibiotics alone; however, osteomyelitis in adults requires a combination of surgical (wound drainage and debridement, removal of infected hardware) and antibiotic therapy. Antibiotic therapy depends on the specific isolate obtained, which must be as precise as possible because empiric treatment for 6–12 weeks would be undesirable. A semisynthetic penicillin (oxacillin, nafcillin) or vancomycin (if MRSA is suspected) plus an aminoglycoside or a third-generation cephalosporin would be adequate until a specific diagnosis is obtained. Chronic osteomyelitis must be treated for as long as 12 weeks of antibiotic therapy, and in some cases, even longer periods of antibiotics may be required. The other MRSA drugs are daptomycin, linezolid, ceftaroline, and tigecycline.


Septic Arthritis

A 73-year-old woman was admitted to your service today with a swollen right knee for the last several days. The knee has an obvious effusion and decreased mobility. There is also redness and tenderness of the knee.


Septic arthritis is an infection of a joint due to virtually any agent. The most common etiology is bacterial; specifically, Neisseria gonorrhoeae, staphylococci or streptococci, but Rickettsia, viruses, spirochetes, etc., may also cause it. Generally, bacterial arthritis is divided into gonococcal and nongonococcal types.

Pathogenesis. Sexual activity is the only significant risk factor for gonococcal septic arthritis. A total of 1–5% of people with gonorrhea will develop disseminated disease, and 25% will have a history of recent symptomatic gonorrhea. Nongonococcal bacterial arthritis is usually spread by the hematogenous route. Additional routes may include bites (animal or human), direct inocula- tion of bacteria into the joint through surgery or trauma, or spread of infection from surround- ing structures such as bone. Even though both normal or damaged joints can get infected, any previous damage to a joint, such as from rheumatoid arthritis or osteoarthritis, previous surgery, prothesis placement, gout, sickle cell disease, or the presence of certain risk factors such as IV drug abuse, diabetes mellitus, or HIV infection can predispose a joint to infection. Any cause of bacteremia can seed the joint because the synovium does not have a basement membrane.


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Note

Gas gangrene is not common; a large referral center may admit 10 cases per year.

However, incidence increases during times of war.


Note

In the past, uterine gangrene was a major complication of improper abortion.

Microbiology. Nongonococcal:

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Table 7-4. Relative Risk of Predisposing Conditions for Infective Endocarditis

High Risk

Intermediate Risk

Low/Negligible Risk

Prosthetic valves*

Mitral valve prolapse with regurgitation

Mitral prolapse without regurgitation

Aortic valve disease

Mitral stenosis

Atrial septal defect

Mitral regurgitation

Tricuspid valve disease

Luetic aortitis

Patent ductus arteriosus

Hypertrophic obstructive cardiomyopathy

Transvenous pacemakers

Arteriovenous fistula

Calcific aortic sclerosis Tetralogy of Fallot

Surgically corrected congenital lesions (no prosthesis) >6 mo after surgery

Coarctation of the aorta

In dwelling right heart catheters (hyperalimentation)

Indwelling right heart and pulmonary artery catheters

Aortocoronary bypass surgery Cardiac pacemakers

Previous infective endocarditis

Nonvalvular intracardiac prosthesis

Marfan syndrome

*Indication for endocarditis prophylaxis.



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Table 7-5. Microorganisms Responsible for Infective Endocarditis

Organism

Incidence, %

Native valves

Streptococcus viridans


50–60

Enterococci

5–15

Other streptococci:

15–20

Staphylococcus aureus

20–30

Staphylococcus epidermidis

1–3

Gram-negative bacilli

<5

Fungi (Candida, Aspergillus, Histoplasma)

<3

Culture negative

<5

In narcotic addicts


Staphylococcus aureus

60–95

Staphylococcus epidermidis

5–10

Streptococci

10–20

Enterococci

8–10

Gram-negative bacilli

4–8

Fungi

4–5

Diphtheroids

1–2

Prosthetic valves

Acutely: first 2 months after surgery

Staphylococcus epidermidis Streptococcus viridans Staphylococcus aureus

40–50 acutely; 10–20 later

5–20 acutely; 40–60 later

15–20 acutely; 20–30 later

Enterococci

5–10

Other streptococci

1–5

Culture negative

<5


Acute infective endocarditis is caused by bacteremia.


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With subacute infective endocarditis, viridans group streptococci is the most common organism. It is associated with low virulence.

Clinical manifestations


Table 7-6. Incidence of Clinical Findings in Infective Endocarditis

Symptoms, %

Signs, %

Chills, 41

Heart murmur or changing murmur, 80–90

Weakness, 38

Fever, 90

Dyspnea, 36

Embolic events, 50

Sweats, 24

Skin manifestations, 50

Anorexia, weight loss, 24

Splenomegaly, 28

Malaise, 24

Septic complications, 19

Cough, 24

Mycotic aneurysms, 18

Skin lesions, 21

Glomerulonephritis, 10

Stroke, 18

Digital clubbing, 12

Nausea, vomiting, 17

Retinal lesions, 5

Chest pain, 16




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Table 7-7. Peripheral Manifestations of Infective Endocarditis

Physical Findings (Frequency)

Pathogenesis

Most Common Organisms

Petechiae (20–30%): red, nonblanching lesions in crops on conjunctivae, buccal mucosa, palate, extremities

Vasculitis or emboli

Streptococcus, Staphylococcus

Splinter hemorrhages (15%): linear, red-brown streaks most suggestive of IE when proximal in nailbeds

Vasculitis or emboli

Staphylococcus, Streptococcus

Osler’s nodes (5–10%): 2–5 mm painful nodules on pads of fingers or toes

Vasculitis

Streptococcus

Janeway lesions (10–15%): macular, red, or hemorrhagic, painless patches on palms or soles

Emboli

Staphylococcus

Roth’s spots (<5%): oval, pale, retinal lesions surrounded by hemorrhage

Vasculitis

Streptococcus


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Complications of infective endocarditis are as follows:

Treatment. Treatment decisions for infective endocarditis should be based on the identification of the organism found in blood culture and its specific antimicrobial sensitivities. Prior to the results of blood cultures, therapy can be started if the patient is very ill or there is very clear evidence of endocarditis such as fever, a clearly new or changing murmur, and embolic phe- nomena. Acceptable empiric therapy would be a combination of an antistaphylococcal drug such as nafcillin (or oxacillin), a streptococcal drug such as penicillin (or ampicillin), and gentamicin. You must alter therapy as soon as a specific microbiologic agent is known. Vanco- mycin and gentamicin are the standard empiric treatment for infective endocarditis.


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Table 7-8. Therapy of Specific Microorganisms Causing Endocarditis

Organism

Medication

Duration

Strep. viridans

Penicillin

Penicillin-allergic: ceftriaxone or vancomycin

Penicillin or ceftriaxone + 2 weeks of gentamicin

4 weeks

4 weeks

4 weeks

Staph. aureus, native valve

(Methicillin-sensitive)


(Methicillin-resistant)

Nafcillin (+ 5 days of gentamicin)

Penicillin-allergic: cefazolin or vancomycin + gentamicin for first 5 days

Vancomycin

4–6 weeks

4–6 weeks


4–6 weeks

Enterococcal

Penicillin (or ampicillin) and gentamicin (vancomycin if penicillin-allergic)

Penicillin-allergic or resistant: vancomycin

and gentamicin

4–6 weeks


4–6 weeks


Note the criteria for surgery in infective endocarditis.

Major criteria


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Figure 7-10. Embolic Features of Acute Endocarditis


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Figure 7-11. Petechial Hemorrhage, an Embolic Phenomenon Due to Septicemia/Endocarditis


Prevention of bacterial endocarditis

The number of cardiac lesions which are an indication for endocarditis prophylaxis has mark- edly diminished over the years. AS, MS, AR, and MR no longer need prophylaxis, even for dental procedures. Prophylactics are indicated when there is both a serious underlying cardiac defect and a procedure causing bacteremia.

Diagnostic criteria for (definite) Lyme are the development of the erythema migrans rash plus at least one late manifestation, as well as lab confirmation of the presence of the organ- ism. Most patients are treated on the basis of the presence of the rash alone.

Serologic testing is the most commonly used test. An ELISA test combined with a Western blot is the standard method of establishing the diagnosis. The problem with serologic testing is that it often does not distinguish between current and previous infection. Also, in early disease when patients have the rash, testing is often negative because patients have not had sufficient time to mount an immune response. In such circumstances, treatment should be given based on strong clinical suspicion, and serologic testing should not be done. Serology will almost always be positive later in the course of the disease.

Treatment. Treat minor symptoms with doxycycline or amoxicillin. Treat the rash, facial palsy, and joint pain with oral doxycycline. Treat more serious manifestations such as heart block, meningitis, myocarditis, or encephalitis with IV ceftriaxone. In other words, all cardiac and serious neurologic manifestations should be treated with IV ceftriaxone.


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Figure 7-12. Erythema-Migrans – Lyme Disease


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Clinical Recall

Which of the following is an indication for prophylactic therapy in the management of infective endocarditis?

  1. Congenital cyanotic heart lesions

  2. Surgically corrected systemic pulmonary shunts

  3. Hypertrophic cardiomyopathy

  4. Mitral valve prolapse with valvular regurgitation

  5. GI surgery


Answer: A


ROCKY MOUNTAIN SPOTTED FEVER

Rocky Mountain spotted fever (RMSF) is a bacterial infection caused by the organism

R. rickettsii.

  1. rickettsii is transmitted by the wood tick. The most common areas are the mid-Atlantic coast, upper South, and Midwest of the United States.

    Clinical Findings.

Symptoms include confusion, lethargy, dizziness, irritability, stiff neck, and GI symptoms. Rash starts by day 6.

Diagnosis is made with specific serology and a skin lesion biopsy. Treat with doxycycline.


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Figure 7-13. Rash of Rocky Mountain Spotted Fever on an Infant


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ACQUIRED IMMUNE DEFICIENCY SYNDROME

Acquired immune deficiency syndrome (AIDS) is caused by the human immunodeficiency virus (HIV). The primary mechanism of HIV is infection of a particular subset of T lympho- cytes called CD4 cells (often called just T cells). Over time, HIV decreases the number of CD4 cells. As a person’s CD4 count drops, he becomes at increasing risk of developing opportunistic infections and certain malignancies.

The mode of HIV acquisition varies around the world.


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Cytomegalovirus (CD4 <50/µL)

Principal Manifestations


Toxoplasmosis (CD4 <100/µL)

Principal Manifestation. Brain mass lesion: headache, confusion, seizures, and focal neuro- logic deficits



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Principal Diagnostic Tests

Treatment. Amphotericin intravenously for 10–14 days at least (with flucytosine), followed by fluconazole orally for maintenance and suppressive therapy.

Prophylaxis. Oral fluconazole is not recommended for general use as a prophylaxis. This is because the incidence of cryptococcal meningitis is too low to demonstrate a mortality benefit with its use.


Vaccinations

All HIV-positive persons should receive vaccinations for pneumococcus, influenza, and hepatitis B. If the CD4 level is >200, even varicella vaccine can be given.


Monitoring the Immune System

CD4 count monitoring and viral load testing can be compared to the staging of cancer in terms of assessing prognosis for the patient. They are indispensable for determining appropri- ate treatment.


CD4 cell count

The CD4 count is the most accurate method for determining what infections or other diseases the patient is at risk for. At the present time the CD4 count provides an assessment of the extent of immunologic damage at the time of diagnosis and is usually the most important factor when deciding the timing of therapy. It is also the strongest predictor of disease progres- sion and survival. Without treatment, CD4 count drops 50–100 cells per year.


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The following is an approximate breakdown of when the risk of certain diseases begins to increase.

CD4 Count 7001,500/μL: Normal

200–500/μL: Oral thrush, Kaposi sarcoma, tuberculosis, Zoster

100–200/μL: Pneumocystis carinii pneumonia, disseminated histoplasmosis and coccidiomycosis

<100/μL: Toxoplasmosis, Cryptococcus, cryptosporidiosis, disseminated herpes simplex

<50/μL: Cytomegalovirus, Mycobacterium avium complex. Progressive, multifocal leukoencephalopathy (PML), CNS lymphoma

In addition to determining the risk of opportunistic infections, the other uses of the CD4 count are to determine:


Viral sensitivity/resistance monitoring

Viral sensitivity testing is done to determine which antiviral medications will be effective in an individual patient. Sensitivity testing should always be done if a patient is failing a combination of medications and a change in therapy is necessary. It should also be done in any pregnant woman who has not been fully suppressed on the initial combination of medications.


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Antiretroviral Therapy


Currently available agents and their major adverse effects

Nucleoside Reverse Transcriptase Inhibitors


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Note

Efavirenz is the only antiretroviral medication that is contraindicated in pregnancy.

A combination therapy (highly active antiretroviral therapy, HAART) should be used with medications having synergistic activity by acting at different sites of the virus replicative process; hence current guidelines recommend two NRTIs (usually tenofovir/emtricitabine or zidovudine/lamivudine) combined with either an NNRTI (efavirenz preferred) or a PI (atazanavir/ritonavir, fosamprenavir/ritonavir, or lopinavir/ritonavir).

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Giving “boosted protease inhibitors” is the practice of giving most protease inhibitors in combination with a low dose of ritonavir (also a PI). Ritonavir given alone as a PI has modest efficacy and significant drug interactions, but when given in a low dose with other PIs, it decreases their metabolism and enables higher drugs levels of the “boosted” PI over a pro- longed period of time. This increases chances of success and also decreases pill burden.

Any regimen that increases the CD4 count and drops the viral load to undetectable amounts or close to undetectable amounts is considered adequate therapy. When starting medication, a drop of at least 50% of viral load in the first month is expected to indicate adequate therapy.


Pregnant Patients

Without treatment, approximately 25–30% of children born to HIV-positive mothers will truly be HIV positive. All children at birth will carry the maternal antibody to the virus and will be positive by ELISA testing, but only 25–30% will remain truly infected.


Breast Feeding

Breast feeding is associated with transmission of virus to the infant. If a pregnant woman is already on antiretrovirals, she should continue on them. She should start immediately regard- less of gestational age. If the woman has high CD4 cells and does not need treatment for herself, combination therapy can end after delivery. The majority of women can deliver with a normal vaginal delivery. Avoid efavirenz in pregnancy.


Postexposure Prophylaxis (e.g., Needlestick Injury)

All persons with serious exposure to blood containing body fluids of HIV-positive patients should receive AZT, lamivudine, and nelfinavir or raltegravir or any other fully suppressive 3-drug combination for 4 weeks. Modify the regimen as needed to ensure compliance. The point is to use any fully suppressive combination for at least 4 weeks; we know zidovudine alone will decrease the risk of transmission by 80%. We don’t know how much the combina- tion will decrease transmission.



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Tetanus

Tetanus is a severe infectious complication of wounds caused by the toxin of Clostridium tetani

(neurotoxin); takes 1–7 days to develop; spore forming, Gram-positive rod.

Clinical Findings. Tonic spasms of voluntary muscles; respiratory arrest; difficulty in swallowing (dysphagia); restlessness; irritability; stiff neck, arms, and legs; headache; lockjaw; flexion of the arms and extension of the lower extremities; and high mortality rate. Diagnosis is clinical.

Treatment is prophylactic:



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Voriconazole and caspofungin are used to treat aspergillosis and some other fungal infections.


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Prerenal Azotemia

Prerenal azotemia is a form of renal insufficiency caused by diminished perfusion of the kidney on any basis. The kidney itself is normal. If the kidney could receive adequate perfu- sion, the BUN and creatinine would normalize. The causes of prerenal azotemia include hypovolemia on any basis (dehydration, burns, poor oral intake, diuretic, vomiting, diarrhea, sweating, hemorrhage), hypotension on any basis (septic shock, cardiogenic shock, anaphylac- tic shock), and third spacing of fluids such as peritonitis, osmotic diuresis, or low aldosterone states such as Addison disease. Addison disease results in intravascular volume depletion, leading to diminished tissue perfusion.



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Diminished perfusion from a decrease in cardiac output also results in prerenal azotemia. Although there may be total body fluid overload with significant edema, all that matters in terms of renal function is how much fluid is still in the vascular space and how much can provide meaningful perfusion of the kidney. With severe CHF, constrictive pericarditis, or coarctation of the aorta, there may be edema and fluid overload, but the kidney is receiving virtually no perfusion, hence the rising BUN and creatinine. This is the concept of effective arterial volume.

The first clue to the diagnosis of prerenal azotemia is a BUN:creatinine ratio of 20:1. There is also a low urine sodium and low fractional excretion of sodium (FeNa <1%) because the kidney perceives the body as being volume-depleted (hence, there will be a vigorous sodium and water reabsorption by the kidney). This results in a very high urine osmolality as well, because the kidney attempts to retain all the water it can in the kidney, and therefore excretes very concen- trated urine. Concentrated urine has a high specific gravity (>1.010) and high urine osmolality (>500). These lab findings are irrespective of the etiology of the prerenal azotemia. In other words, the BUN:creatinine ratio rises to 20:1, urine sodium is low, and the urine osmolality is high no matter what the etiology of the decreased perfusion or hypotension.

Low albumin states also lead to decreased renal perfusion. Nephrotic syndrome and other malabsorptive states lead to a low albumin level. This leads to renal failure.


Renal artery stenosis

Renal artery stenosis, especially if bilateral, results in high BUN and creatinine with a high BUN:creatinine ratio. Although systemic BP may be markedly elevated, the result is still a form of prerenal azotemia. There is markedly diminished renal perfusion because of the obstruction in the renal artery. The systemic BP does not matter; all that matters is how much is getting to the kidney. Hence, to the kidney, renal artery stenosis functions like hypotension. This effect is greatly exaggerated with the use of ACE inhibitors, which markedly diminish renal perfusion. This is because of the extremely high aldosterone state in renal artery stenosis.


Hepatorenal syndrome

Hepatorenal syndrome is renal failure based entirely on the presence of hepatic failure. The kidneys are normal. The rise in BUN and creatinine is believed to be due to an intense vaso- constriction of the afferent arteriole, causing decreased renal perfusion.

Treatment is correction of the underlying liver disease. Midodrine, an alpha agonist, and octreotide may be beneficial, but the best treatment is liver transplantation.


ACE inhibitor effect on the kidney

ACE inhibitor–induced renal failure is caused by vasodilation of the efferent arteriole. Angiotensin has a significant vasoconstrictive effect on the efferent arteriole; ACE inhibitors block this, causing


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a decreased GFR that is usually transient. However, in the elderly, diabetics, hypertensives, or patients with baseline renal disease such as from myeloma, an ACE inhibitor can produce quite a marked decrease in renal function. Hence, if there is underlying renal insufficiency, there can be a rise in BUN and creatinine after initiating an ACE inhibitor. In patients with bilateral renal artery stenosis, observe for severe decline in renal function after an ACE inhibitor has been initiated.

Despite the ability of ACE inhibitors to potentially worsen renal function, their overall effect on the kidney is to diminish the rate of progression to uremia and renal failure. This beneficial effect is most likely secondary to the decrease in intraglomerular hypertension. ACE inhibitors and angiotensin receptor blockers decrease hypertension inside the glomerulus. ACE inhibi- tors decrease proteinuria by 35–45%. ACE inhibitors produce a brief decrease in GFR in the short-term, with a long-term beneficial effect on decreasing proteinuria and the rate of progression of renal failure. This is particularly true in patients with diabetes.


Postrenal Azotemia

Postrenal azotemia is caused by any decrease in the outflow of urine. The precise etiology of the obstruction is not particularly relevant when it comes to the degree of renal failure. All that matters is that there is an obstruction bilaterally to the flow of urine out of the kidney.

Initially, BUN and creatinine will elevate in a ratio 20:1 as it does with prerenal azotemia. There will also be a low fractional excretion of sodium (FeNa) and low urine sodium. When the obstruction continues for such a long time that there is permanent damage to the kidney and the kidney tubule cells die, then the BUN:creatinine ratio will lower to 10:1, as is seen in acute tubular necrosis (ATN). Early diagnosis is, therefore, essential. Complete recovery is pos- sible until 10–14 days of obstruction.

ATN is the most common cause of AKI (intrinsic) in hospitalized patients.

The diagnosis of postrenal azotemia is determined by finding a distended bladder on examina- tion, bilateral hydronephrosis on renal sonogram or CT scan, or by finding large volumes of urine in the bladder after passing a Foley urinary catheter. After urinating (voiding), there should be no more than 50 mL of urine left in the bladder. If this post-void residual is mark- edly elevated, it implies an obstruction to the flow of urine out of the bladder.

Treatment is based on relieving the cause of the obstruction.


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Intrarenal: Tubulointerstitial Disease


Acute tubular necrosis

Acute tubular necrosis (ATN) is acute renal failure on the basis of tubular damage (as opposed to glomerular damage), or simply decreased perfusion of the kidney or drainage out of the kid- ney. About 85% of acute renal failure is secondary to intrinsic renal disease such as ATN.

Diagnosis. The initial clue is a BUN:creatinine ratio close to 10:1; by itself this ratio simply implies the damage is intrarenal (inside the kidney itself), as opposed to abnormalities of perfusion (prerenal) or drainage (postrenal). Further clues to the diagnosis of ATN are high urine sodium (>40), high fractional excretion of sodium (>1%), and low urine osmolality (<350). This is because tubular cells are responsible for forming either concentrated or dilute urine. If the tubular cells die from ischemia, then the kidney can neither concentrate nor dilute the urine. Dead cells don’t work.


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Note

Other Meds


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Respiratory acidosis or ’normalization’ of pH in patients with acute asthma exacerbation may be an indication for intubation.

If, 3 days after hospitalization the patient is improving and you decide to send her home, her drug regimen would likely be oral prednisone taper, albuterol inhaler, steroid inhaler.

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Suppose the patient returns 3 months later for follow-up. She needs documentation of asthma for her work. You would do a PFT to document the asthma, and confirm that her basic asthma regimen should be inhaled steroids daily and albuterol inhaler as needed.

For testing purposes, the guidelines are simplified into the following classifications.


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Allergic Bronchopulmonary Aspergillosis

Allergic bronchopulmonary aspergillosis (ABPA) is an allergic lung reaction to a fungus (most commonly Aspergillus fumigatus) seen in some patients with asthma or cystic fibrosis. Other fungi, including Penicillium and Candida, can cause an identical illness. In some peo- ple, the effects of the allergic reaction combine with the effects of the fungus to damage the airways and lungs further.

Both of these processes are defined by nonreversible obstruction of the airways. This is the pathognomonic differentiating finding on PFTs when compared with asthma.



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Cigarette smoking is a cause of COPD, with 10–15% of smokers developing COPD (80–90% of COPD patients are cigarette smokers). COPD symptoms usually begin after at least 20 pack-years of tobacco exposure. The number of pack-years of smoking correlates to

the reduction of FEV1. The fact that a small percentage (10–15%) of smokers develops COPD suggests that other factors may be involved in the pathogenesis. Air pollution, airway infec- tions, and allergies can lead to bronchitis.

α1-antitrypsin deficiency is a rare hereditary autosomal recessive disease that can cause emphysema and liver abnormalities.

Pathogenesis. After long-term exposure to cigarette smoke, inflammatory cells are recruited in the lung. These inflammatory cells in turn secrete proteinases, which may lead to air space destruction and permanent enlargement. Eventually, decreased elastic recoil (mainly in emphysema) and increased airway resistance (mainly with chronic bronchitis) occur.

Physical Examination. In emphysema, distant breath sounds will be heard on auscultation. In chronic bronchitis, there may be evidence of rhonchi and wheezes to auscultation. Signs and symptoms of right heart failure (cor pulmonale) and clubbing can also be seen on physical examination in COPD.


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Figure 9-9. Clubbing of the Fingers Seen with Chronic Hypoxemia


In chronic bronchitis, increased pulmonary markings can be seen on chest x-ray; in emphy- sema, hyperinflation of bilateral lung fields with diaphragm flattening, small heart size, and increase in retrosternal space can be seen.

Cor pulmonale in COPD is associated with chronic pulmonary hypertension.

Diagnosis. PFTs are the diagnostic test of choice. On PFT, a reduction in FEV1/FVC ratio and FEF25–75 occurs. RV and TLC are usually increased in COPD. Emphysema will have a decreased DLCO, whereas chronic bronchitis will generally have a normal DLCO.

After a bronchodilator is given, you would expect the FEV1/FVC to remain the same or improve minimally.

Complications. Hypoxemia with nocturnal desaturation is sometimes seen. Secondary erythro- cytosis can result from chronically low Po2. Pulmonary hypertension is a complication that can lead to cor pulmonale and subsequent right heart failure. Chronic ventilatory failure and CO2 retention are seen in chronic bronchitis early and at the end stages of emphysema.


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Management of Stable Phase COPD. The goal in treatment is to treat airway inflammation and bronchospasm, reduce a irway resistance and work of breathing, and improve gas exchange

and ventilation-perfusion (V/Q) mismatching.

Anticholinergic agents (ipratropium bromide [Atrovent®] and tiotropium) are the first-line drugs in COPD. These agents are given via MDI and control airway caliber and tone. Anticho- linergic agents can be used synergistically with β2-adrenergic agonists in patients with COPD.

β2-adrenergic agonists (albuterol) are used after anticholinergic agents. The inhaled route is the preferred administration.

Beta agonists are not first-line agents in the management of COPD because many of the patients have underlying heart disease and the tachycardia commonly associated with these agents may precipitate heart failure.

Chronic inhaled corticosteroids are reserved for severe cases of COPD.

Theophylline, a xanthine derivative, may be added to the regimen if beta-2 agonists and anticholinergics are not effective in managing the symptoms of chronic obstructive lung disease. Remember that theophylline has significant toxicity. Symptoms include nausea and vomiting, palpitations, and tremulousness. Death can occur from theophylline toxicity from cardiac arrhythmias.

The list of drug interactions with theophylline is significant. Theophylline levels increase with fluoroquinolones, clarithromycin, H2-blockers (cimetidine, ranitidine), certain beta blockers and calcium channel blockers. Theophylline levels decrease (due to increased clearance) with rifampin, phenytoin, phenobarbital, and smoking.

Despite the above treatments, the only interventions which have been shown to decrease mortality in patients with COPD are home oxygen and smoking cessation.

Home oxygen therapy is given to patients with hypoxemia (Pao2 <55 mm Hg or saturation

<88%), and the goal is to try to keep the O2 saturation >90% as much as possible, especially at night when patients generally desaturate. Patients with cor pulmonale will benefit from home

oxygen when Pao2 <59 mm Hg. A special category is the patient who desaturates with exercise; in that case, intermittent oxygen will be beneficial.

All patients with COPD must have the pneumococcal vaccine (Pneumovax®) every 5 years and the influenza vaccine yearly. They should also receive the H. influenzae vaccine if they were not previously immunized.

Several trials have failed to find a beneficial effect for the regular chronic use of inhaled corticosteroids in patients with COPD.

Management and Treatment of COPD Exacerbation (Acute Setting Treatment). Acute exacerbation of COPD is considered acute worsening of the patient’s respiratory symptoms (increased dyspnea, increased sputum volume, production of purulent sputum) that necessi- tates a change in medications.

The most common causes of COPD exacerbation are viral lung infections. Other precipitating causes that should be sought out are bacterial infections, heart failure, myocardial ischemia, pulmonary embolism, lung cancer, esophageal reflux disease, and medications (e.g., beta-blockers).


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Initial Management

  1. Measure O2 saturation via pulse oximetry (on the spot) to determine oxygen saturation.

  2. ABG determination is very useful to identify the level of hypercapnia and thus the severity of exacerbation.

  3. Chest x-ray is expected in all patients with COPD exacerbation to identify pulmo- nary infiltrates consistent with pneumonia. It may also show evidence of pulmo- nary edema, indicating possible heart failure as the cause of the exacerbation.

  4. Spirometry (and other PFT evaluation) is not helpful in COPD exacerbation because measurements (FEV1, etc.) have not been shown to correlate well with the severity of the exacerbation.

  5. In the acute setting, check levels in patients on chronic treatment with theophyl- line. Drugs like erythromycin, cimetidine, and ciprofloxacin may decrease theophylline clearance and cause theophylline toxicity.

  6. Other tests as part of the initial evaluation of COPD exacerbation might include CBC (looking for elevated WBCs and polycythemia); ECG (looking for new arrhythmias, e.g., atrial fibrillation that may precipitate heart failure and exacerbate COPD).

  7. Any significant changes of hypercapnia or hypoxemia from baseline should prompt consideration for admission to the hospital. Also, patients on home O2 who have exacerbation, and those with severe symptoms, should be hospitalized.

  8. Consider intubation and mechanical ventilation in patients with decreased levels of consciousness, cyanosis, or hemodynamic instability and in those with persistent hypoxemia despite adequate oxygen supplementation.

Specific Therapy

  1. Oxygen supplementation should be titrated to ~90% saturation on the pulse oximeter. The first and foremost concern is to deliver adequate oxygenation. In COPD exacerbation, we should be concerned about CO2 retention as a secondary

    issue.

  2. Inhaled bronchodilators are the most effective medications to improve airway diameter (the drugs of choice). In acute COPD exacerbations, use both beta- agonists (albuterol) and anticholinergics (ipratropium) simultaneously. Trials have shown that administration of these drugs by a nebulizer or metered dose inhaler (MDI) with a spacer is equally efficacious. Patients with severe exacerba- tions are unable to hold their breath for more than a few seconds and are thus initially treated with nebulizers and then switched to the MDIs.

  3. Systemic corticosteroids have now been shown in multiple trials to shorten the recovery time of lung function and decrease the length of stay in patients with COPD exacerbation. Corticosteroids may be given intravenously or orally because the efficacy is similar in both modes of administration. The equivalent of 60 mg prednisone appears to be the sufficient starting dose and is usually continued for 2 weeks. It makes sense clinically to start patients who have a severe exacerbation with IV methylprednisolone (it is difficult for these patients


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to take oral meds), then change to oral prednisone as they improve. Inhaled corticosteroids have not been shown to improve outcomes in patients with COPD exacerbation and cannot be substituted for systemic corticosteroids.

  1. Antibiotics seem to be beneficial in COPD exacerbations despite “normal” chest radiograms. Patients with productive, purulent cough benefit the most because they are more likely to have an underlying bacterial infection. Antibiotics commonly used are second-generation macrolides (clarithromycin, azithromy- cin), extended-spectrum fluoroquinolones (levofloxacin, moxifloxacin), cephalo- sporins (second- and third-generation), and amoxicillin clavulanate.

  2. There is no real benefit to using IV aminophylline. However, if the patient is using theophylline on a chronic basis (in outpatient setting), it should be continued during the exacerbation because abrupt discontinuation may worsen symptoms.

  3. Always avoid opiates and sedatives because they may suppress the respiratory system.

  4. Although specific chest physiotherapy (postural drainage, etc.) has not been shown to benefit patients with exacerbation, they should be encouraged to increase activities as tolerated to prevent deconditioning.

  5. Counseling the patient on smoking cessation in the hospital setting is the single most important intervention.

  6. Teaching the patient optimal use of MDIs has been shown to reduce readmission rates.

Prognosis. FEV1 is the best predictor of survival (the higher the FEV1, the better the survival and the less symptomatic the patients). The rate of FEV1 decline may also predict survival because patients with a faster decline will have increased morbidity. Patients that have a FEV1

≤25% will usually complain of dyspnea at rest.

Tobacco cessation is the only means of slowing progression of COPD and the decrease in FEV1.

It is very important that patients with COPD have vaccinations against Pneumococcus with a booster at 5 years and yearly for influenza. Some experts consider the H. influenzae vaccine mandatory.

Going back to our patient, you would likely find decreased DLCO on her PFTs. Treatment of this patient in the acute exacerbation would be systemic steroids, antibiotics, and bronchodilators, with O2 as needed. Treatment once she goes home would be ipratropium inhaler and home O2.

To assess the severity of this patient’s disease, measure FEV1.


Bronchiectasis

A 17-year-old girl is admitted to the hospital with a right lower lobe pneumonia. She gives you a history of recurrent pneumonias, some of which have kept her in the hospital for weeks, and of chronic productive cough that occurs every day. Her parents inform you that she has had “loose stools” since childhood. On the examination she is thin and in distress. There are diminished breath sounds on the right lower lobe with rhonchi.


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The phenomenon produced by AP film is no different than holding your hand in a light shined against a wall. The farther your hand is away from the wall, the larger your hand’s shadow will appear.



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The right hemidiaphragm will appear higher on a lateral

  1. ray and a PA film because the liver pushes it upward.

    Technical Aspects of Normal Film Quality

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If maximal medical therapy is ineffective in controlling intraocular pressure, consider surgery. Laser trabeculoplasty or surgical trabeculectomy are the most commonly per- formed procedures.


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Closed-Angle Glaucoma

Closed-angle glaucoma is often an ophthalmologic emergency precipitated by the use of medications with anticholinergic properties.

It presents with an eye that is red, painful, hard to palpation, and associated with a fixed midpoint pupil. The cornea has a hazy cloudiness, and there is marked diminishment of visual acuity.

Treatment of acute angle-closure glaucoma is an ophthalmologic emergency. Use IV acetazolamide, urea, and osmotic diuretics such as mannitol and glycerol.

Pilocarpine can be used to open the canal of Schlemm, and beta-blockers are used to decrease humor production. If these medical therapies are ineffective, laser trabeculoplasty can be performed.


CATARACTS

Cataracts are opacifications of the lens. They are slowly progressive, with a blurring of vision occurring over months to years. Glare from the headlights of cars is particularly a problem when driving at night. Color perception is reduced in general. The etiology of cataracts is unknown, although there is an association with cigarette smoking.

Mature cataracts can be easily seen on physical examination. Earlier-stage disease is seen with a slit lamp.

There is no medical therapy for cataracts. Surgical removal with the placement of an intraocu- lar lens is the standard of care.


CONJUNCTIVAL DISEASES


Conjunctivitis

Conjunctivitis can occur from any infectious agent, including bacteria, viruses, and fungi.

Treat bacterial conjunctivitis with a topical antibiotic such as erythromycin ointment, sulfacetamide drops, or topical fluoroquinolones.

Treat viral conjunctivitis symptomatically with topical antihistamine/decongestants. There is no specific microbiologic treatment.


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Subconjunctival Hemorrhage

Subconjunctival hemorrhage is more dangerous in its appearance than in its actual damage to vision or even the eye itself. The most common cause is trauma, particularly in the presence of thrombocytopenia. The collection of the hematoma stops at the limbus, which is the anatomic connection between the conjunctiva and the cornea. Because this prevents the blood from covering the cornea, there is no impairment of vision.

There is no intraocular or intravitreal damage and hence no impairment of vision. No specific therapy is necessary.


KERATITIS

Keratitis refers to any infection or inflammation of the cornea. Usually, keratitis happens as a result of trauma to the cornea with the inoculation of bacterial or fungal elements into the cornea.


Herpes Simplex Keratitis

Herpes simplex keratitis is characterized by severe pain in the eye and a sensation that something is caught under the eyelid.

Diagnosis is based on finding a characteristic dendritic pattern over the cornea on fluorescein staining of the eye with examination under a blue light.

Treatment is oral acyclovir, famciclovir, or valacyclovir, plus topical trifluridine 1% solution or idoxuridine.

Note that oral and topical steroids should never be used in an attempt to relieve the inflammation of herpes simplex keratitis. That can markedly worsen the growth of the virus (acting as “fertilizer”).


PERIORBITAL CELLULITIS

Cellulitis is caused by Staphylococcus aureus or Streptococcus invading the dermis and subcuta- neous tissues surrounding the eye.

Treatment is an antistaphylococcal penicillin such as oxacillin or nafcillin. In cases of penicillin allergy, use a first-generation cephalosporin such as cefazolin.


UVEITIS

Uveitis occurs when the structures of the uveal tract (the iris, ciliary body, and choroid) become inflamed. It is caused by various systemic inflammatory conditions, such as psoriasis, sarcoidosis, syphilis, Reiter syndrome, and IBD.

Uveitis leads to a painful, red eye with marked photophobia. One clue to diagnosis is pain that occurs even when shining a light in the unaffected eye. This is because of the consensual light reflex in which the affected pupil will constrict even when light is shined in the normal eye.



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Diagnosis is made by slit lamp examination. Inflammation of the iris, ciliary body, and choroid is visible. Inflammatory cells may accumulate on the inside of the cornea after they precipitate out of the aqueous humor, rather like an accumulating snowfall. These focal collections are called keratic precipitates.

Basic management, despite the varied underlying conditions, is to treat with topical or systemic steroids.


Clinical Recall

A 32-year-old man presents with redness of his eyes, marked photo- phobia, and normal conjunctiva. Which of the following is the best initial treatment?

  1. Topical corticosteroids

  2. Corticosteroids

  3. Topical acyclovir

  4. Oral idoxuridine

  5. Topical trifluridine


Answer: A


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A

ABCDE discharge recommendations, in ACS, 145

Abdominal aortic aneurysm, screening for, 8

Abdominal imaging ultrasound, 460

x-rays, 460–462

Abdominal pain, lead poisoning and, 384 Abscess

brain, 232–233

lung, 237–238

perinephric, 259–260 Absence (petit mal) seizures, 412 Acanthocytes, 205

Accelerated atherosclerosis, in end-stage renal disease, 299

Acetaminophen, for osteoarthritis, 78 Acetaminophen toxicity, 378–379 Acetylcholine, in dementia

management, 428

Achalasia, 86–87

Achlorhydria, 97

Acid-base disturbances, 305–308

Acid-fast bacilli (AFB), in tuberculosis testing, 244, 245

Acidosis

diabetic ketoacidosis, 43–44 in drowning victims, 401 metabolic, 306–307

renal tubular, 308–310

respiratory, 308

in salicylate toxicity, 386 Acids, toxic exposure to, 381

contraindicated management, 382

Acne, 454

Acquired immune deficiency syndrome (AIDS), 273–278

antiretroviral therapy for, 277–278

breast feeding and, 278 immune system monitoring in,

276–277

mode of acquisition, 273 opportunistic infections in, 273–275 postexposure prophylaxis for, 278 pregnancy and, 278

Acromegaly, 15–17

Actinic keratosis, 448

Acute bacterial pyelonephritis, 259 Acute bronchitis, 237

Acute coronary syndrome (ACS), 137–149 chest pain quality in, 126 complications of, 146–148

discharge medications after, 145–146 nonatherosclerotic, 148–149

NSTEMI, 137, 138–140

operational classification, 137–138

STEMI, 137, 140–146

unstable angina, 137, 138–140

in women, 126

Acute idiopathic polyneuropathy (Guillain-Barré syndrome), 420–421

Acute kidney injury (AKI), 281–290 Acute leukemia, 209–210

lymphocytic, 209

myelogenous, 209

Acute pancreatitis, 116–118

Acute pericarditis, 272–273

Acute renal failure (ARF), 281–290 Acute respiratory compromise/distress,

evaluating, 330–331

Acute respiratory distress syndrome (ARDS), 357

in drowning victims, 402 hospital admission and, 332

Acute tubular necrosis (ATN), 285–286 Adalimumab (Humira), 67

Adams-Stoke attacks, 178

Addison disease, 54–55

Adefovir, for hepatitis infection, 250 Adenocarcinoma, of lung, 358 Adenomas

pituitary, 13–17

thyroid, 31

Adenomatous polyposis coli (APC) gene, 112

Adenosine, adverse effects of, 189 Adenosine stress test, 135

Adjuvant therapy, in STEMI, 144–145 Adrenal androgen excess, syndromes of, 53 Adrenal crisis, 56

Adrenal glands

cortical regions of, 48–49 diseases of, 48–57

hyperfunctioning, 49–54

hypofunctioning, 54–57

hypopituitarism and, 18 Adrenal hyperplasia

congenital, 52–53

in Cushing syndrome, 49–51 Adrenal insufficiency, 54–56

Adrenal neoplasia, in Cushing syndrome, 49–51

Adrenocorticotropic hormone (ACTH) Addison disease and, 54–55 Cushing syndrome and, 49–51 hypopituitarism and, 18

Adriamycin, bleomycin, vinblastine, dacarbazine (ABVD) therapy, 216

Adult polycystic kidney disease, 311 Adult respiratory distress syndrome.

See Acute respiratory distress syndrome (ARDS)

Advanced cardiac life support (ACLS) algorithm, 187, 362

Afterload increase/reduction,

in HOCM, 170

Age, as IHD risk factor, 132

Age-related macular degeneration (ARMD), 467–468

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Air flow/movement, measurement of, 321 Albumin

in hypoparathyroidism, 39 in prerenal azotemia, 283

Alcohol abuse. See also Ethylene glycol poisoning

hypoglycemia and, 48

isopropyl alcohol ingestion, 380 methanol poisoning, 379–380

screening for, 9

Alcohol withdrawal-related syndromes, 390–391

Alcoholic hallucinosis, 390 Alcohols

clearance time, 378

dialysis and, 380

Alkaline phosphatase, primary biliary cirrhosis and, 121

Alkalis, toxic exposure to, 381 contraindicated management, 382

Alkalosis

metabolic, 305–306

respiratory, 306

All-trans-retinoic acid (ATRA), 210 Allergic asthma, 335

Allergic bronchopulmonary aspergillosis (ABPA), 339

Allergic cross-reactivity, with penicillins, 226

Allergic interstitial nephritis (AIN), 286–287 Allergies

anaphylaxis and, 402

asthma and, 335

Allopurinol, gout and, 79, 80

Alopecia areata, 453

Alpha-1 antitrypsin deficiency (AATD) in COPD, 340

liver disease and, 123 Alpha-adrenergic blockers, 318

as antihypertensive, 318

Alpha thalassemia, 198, 199

Alport syndrome, 295

Alveolar-arterial gradient (PAo2–Pao2), 326–327

Alveolar diffusing capacity (DLCO), 322, 324

Alzheimer disease, 427 Aminoglycosides

acute renal failure and, 289 gram-negative bacilli and, 228

as myasthenia gravis therapy, 423


Aminophylline therapy, 336 Amiodarone

abnormal thyroid function caused by, 29

adverse effects, 189

for cardiovascular disease, 188

for ventricular tachycardia, 367, 368 Amnesia, head trauma and, 391 Amoxicillin, for gram-positive cocci, 226 Amphetamines, clearance time, 378 Amphotericin B, acute renal failure and, 289 Ampicillin

for gram-positive cocci, 226 for meningitis, 230

Amyl nitrate, effect on systolic murmurs, 166

Amylase test, in acute pancreatitis, 117 Amyloidosis, 295–296

Amyotrophic lateral sclerosis (ALS), 423–424

Anaerobic bacteria, antibiotics for, 228 Analgesic nephropathy, 290

Anaphylaxis, 402

Anaplastic carcinoma, of thyroid, 32 Anemia, 193–195

aplastic, 208–209

in end-stage renal disease, 299 etiology, 193

hemolytic, 201–208

macrocytic, 200–201

microcytic, 196–199

patient evaluation algorithm, 195 Anesthetics, malignant hyperthermia

and, 399

Angina

Prinzmetal, 149

stable, 126, 133–136

unstable, 137, 138–140 Angiography

in gastrointestinal bleeding, 115 in IHD, 136

pulmonary, 353–354

in subarachnoid hemorrhage, 396 in unstable angina/NSTEMI, 140

Angioplasty

acute renal failure and, 289

for cerebrovascular accident, 411 Angiotensin-converting enzyme (ACE)

inhibitors, 283–284

in acute coronary syndrome, 146 as antihypertensive, 317


in congestive heart failure, 154–156, 158 Angiotensin receptor blockers (ARBs)

as antihypertensives, 317

for congestive heart failure, 154, 155

Animal bites, 402, 403–404 Anion gap

in renal acidosis, 306–307

in renal tubular acidosis, 309 in salicylate toxicity, 386

Ankylosing spondylitis (AS), 74–75 sacroiliitis in, 75

Anterior cerebral artery (ACA) occlusion, 409

Anterior pituitary, diseases of, 13–19 Anterior-posterior (AP) chest x-rays, 455 Anterior spinal artery occlusion, 407 Anterograde memory loss, head trauma

and, 391

Anti-tissue transglutaminase antibody (IgA), 108, 109

Antiarrhythmics, 189

adverse effects, 189

Antibiotic-associated diarrhea (AAD), 105–106

Antibiotics

in acute renal failure, 289 for anaerobic bacteria, 228 in asthma, 336

in COPD, 343

diarrhea caused by, 105–106 in diarrhea management, 104

for gram-negative bacilli, 227–228 for gram-positive cocci, 225–227 in infectious disease, 225–228

in radiation injury management, 401 for skin MRSA, 228

Anticardiolipin antibodies, 65 Anticholinergic drugs

in asthma, 336

in COPD, 341

Anticholinergic poisoning, 388–389 Anticholinesterase inhibitors, in dementia

management, 428 Anticholinesterase therapy, for myasthenia

gravis, 422

Anticipation, Huntington disease and, 428 Anticoagulants. See Warfarin Anticonvulsant therapy, 413

Antidiuretic hormone (ADH) diabetes insipidus and, 19–21

excess of, syndromes associated with, 22



USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.

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inappropriate secretion of, syndrome of, 22

pituitary gland and, 11 Antiemetics, in radiation injury

management, 401

Antifungals, 439

Antihistamines, for urticaria, 435 Antihyaluronic acid (AHT) test, 294 Antihypertensive medications, 316–318 Antineutrophil cytoplasmic antibodies

(ANCAs), 64

Wegener granulomatosis and, 82 Antinuclear antibodies (ANAs)

in drug-induced lupus, 70

in rheumatologic disease evaluation, 63–64

in scleroderma, 72

Antiphospholipid antibody syndrome, 65 Antiplatelet therapy

in cerebrovascular accident, 411 in STEMI, 144–145

in unstable angina/NSTEMI, 139 Antipsychotics, in alcohol withdrawal

management, 390, 391

Antiretroviral therapy, 277–278 Antistaphylococcal antibiotics

for bacterial infections of skin, 441 for furuncles and carbuncles, 442

Antistreptolysin (ASO) test, 294 Antithrombin therapy

in STEMI, 145

in unstable angina/NSTEMI, 139 Antivenin, 404

Anxiety, hypertension and, 313 Aortic coarctation, 316

Aortic dissection, 128–129

Aortic regurgitation, 166–167

Aortic stenosis, 164–165

differential diagnosis, 165 effects of maneuvers on, 166

Aortic valve sclerosis, in aortic stenosis differential diagnosis, 165

APACHE score, in acute pancreatitis, 117 Apixaban, 372

Aplastic anemia, 208–209

Argyll Robertson pupil, in syphilis, 253 Arnold Chiari malformation, 406 Arrhythmias. See also Dysrhythmias

digoxin toxicity and, 387 drug therapy for, 189

in hypothermia, 399


supraventricular, 178–183, 367–368 torsade de Pointes, 186–187 ventricular, 184–185

ventricular fibrillation, 365 Arterial blood gases (ABGs)

in acute respiratory compromise/ distress, 331

in adult respiratory distress syndrome, 357

in asthma, 335–336

in carbon monoxide poisoning, 380, 381

in COPD, 342

disturbances in, 326–327

in pulmonary thromboembolism, 352 Arteritis, temporal, 83, 417

Arthritis

evaluating patient with, 61–62 psoriatic, 74, 76

reactive, 74, 75

rheumatoid, 65–68

septic, 81, 261–262 Arthrocentesis, septic arthritis and, 81 Arthropathies

crystal-induced, 78–80

migratory, 61

seronegative, 73–76

Asbestosis, 348–349 Ascites

in acute pancreatitis, 117 in liver disease, 119–120

Aspergillosis, 279

allergic bronchopulmonary, 339 Aspiration biopsy, in lung cancer, 359 Aspirin

in acute coronary syndrome, 145 in cerebrovascular accident, 411 in unstable angina/NSTEMI

management, 139 Aspirin (salicylate) toxicity, 386–387 Aspirin-sensitive asthma, 335

Astemizole, 435

Asthma, 334–338

Asystole, management of, 364 Atelectasis, 360

Atheroembolic disease, in acute renal failure, 289

Atherosclerosis, in end-stage renal disease, 299

Atlantoaxial subluxation, 67, 68

Atopic asthma, 335

Atopic dermatitis, 451–452


Atrial dysrhythmias, 369–373 Atrial fibrillation (A-fib), 179–183,

369–373

management algorithm, 181

patient evaluation, 182

Atrial flutter, 179, 369–373

Atrial tachycardia, 366, 370

multifocal, 179

Atrioventricular (AV) block, 176–178, 373–374

Atropine, contraindicated in asystole, 364 Autoimmune diseases

hemolytic anemia, 204–205

pemphigus vulgaris, 434

Autoimmune pancreatitis, 118 Automatic implantable cardioverter/

defibrillator (AICD), 161

Autonomic neuropathy, 46 Avian influenza, as pneumonia

predisposition, 239 Azathioprine, for inflammatory bowel

disease, 100 Azotemia

in acute renal failure, 282 postrenal, 284

prerenal, 282–284


B

“B” symptoms, of Hodgkin disease, 215, 216

B-type natriuretic peptide (BNP)

in congestive heart failure diagnosis, 154

in pleural effusion diagnosis, 331

Bacillus anthracis, as pneumonia predisposition, 239

Bacillus Calmette-Guérin (BCG) vaccination, 243

Bacillus cereus, infectious diarrhea and, 103

Background retinopathy, 46, 465 Baclofen

in ALS, 423

in multiple sclerosis therapy, 426 Bacterial infection. See also under

Infectious disease

brain abscess and, 232

endocarditis. See Infective endocarditis of skin, 441–443

Bacteriuria, in renal disease diagnosis, 298



USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.


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Bacteroides infection, brain abscess and, 232 Baker cyst, 68

Barbiturates

clearance time, 378

overdose, 383

Barium studies, 461

in diffuse esophageal spasm, 88 esophagitis and, 89

in inflammatory bowel disease, 108 Barrett esophagus, 94

Bartter syndrome, 53 Basal cell carcinoma, 450 Basophilic stippling, 198

Below-the-knee DVT, 356 Bence-Jones protein

in acute renal failure, 288 in nephrotic syndrome, 296

Benedikt syndrome, 410 Benign essential tremor, 431

Benign paroxysmal positional vertigo, 416 Benzodiazepines

in alcohol withdrawal management, 390 clearance time, 378

overdose, 383

Berger disease, 294

Beta-adrenergic agonists for asthma, 336

for COPD, 341

Beta blockers

in acute coronary syndrome, 145 adverse effects, 189

as antihypertensive, 317

in asthma, 336, 337

atrial dysrhythmias and, 374

in cardiovascular disease, 189–190 in congestive heart failure, 155

in COPD, 341

in unstable angina/NSTEMI, 140 for ventricular fibrillation, 368

Beta-lactam antibiotics, 443

Beta-lactamase inhibitor, 227

Beta thalassemia, 199

Bi-level positive airway pressure (BiPAP), 333

Bicarbonate therapy

in barbiturate toxicity, 383 in salicylate toxicity, 386

in tricyclic antidepressant toxicity, 388 Biguanides (metformin), 41, 42

Binswanger disease, 427

Biologic agents, in RA management, 67


Bite injuries, 402–404

Biventricular pacemaker, 158 Bleeding

in end-stage renal disease, 299 evaluation algorithm, 219

gastrointestinal, 113–116 Blisters

in burn injuries, 397, 398

disease involving, 434–435

toxidromes and, 376 Blood products

in anemia management, 194

in radiation injury management, 401 Blood urea nitrogen (BUN), 281, 282–288 Body temperature, in heat disorders, 398 Bone and joint infections, 260–262

imaging studies in, 463

Bone marrow, radiation injury to, 400, 401 Bone marrow transplantation

allogenic, in acute leukemia, 210 in aplastic anemia, 209

autologous, in multiple myeloma, 213 in radiation injury management, 401

Bordetella pertussis, as pneumonia predisposition, 239

Borrelia burgdorferi, 270

Botulinum toxin, in achalasia therapy, 87 Botulism, myasthenia-like illness and, 422 Bovine spongiform encephalopathy,

dementia and, 427

Bradycardia, 176, 373–374

management algorithm, 375

Brain abscess, 232–233

Brain imaging, in dementia assessment, 428 Brain natriuretic peptide. See B-type

natriuretic peptide (BNP)

Breast cancer

in males, hypogonadism and, 58 screening for, 2

Breast feeding, by HIV-positive patients, 278

BRIT mnemonic, 429 Bromocriptine

acromegaly and, 17

hyperprolactinemia and, 14, 15

Bronchietasis, 343–344

Bronchitis, 237 Bronchoalveolar lavage

in idiopathic pulmonary fibrosis, 346 in Pneumocystic jiroveci identification,

273


in Pneumocystis pneumonia diagnosis, 241

Bronchodilator reversibility, 324 Bronchodilators, in COPD, 342 Bronchogenic carcinoma, 358–360 Bronchopulmonary aspergillosis,

allergic, 339 Bronchoscopy

in burn injury assessment, 397 in lung cancer, 359

Brown-Séquard syndrome, 408 Bullae, necrotizing fasciitis and, 443 Bullous/blistering diseases, 434–435

Bullous pemphigoid, 434

Burn injuries, 396–398


C

C-11/C-17 hydroxylase deficiency, 52–53 Cabergoline

acromegaly and, 17

hyperprolactinemia and, 14, 15

CAGE questionnaire, 9

Calcinosis, in CREST syndrome, 71 Calcitonin

in calcium regulation, 35 in hypercalcemia, 33, 35

in primary hyperparathyroidism, 37 in thyroid carcinoma, 32

Calcium, regulation of, 33, 35 Calcium channel blockers

as antihypertensive, 317 atrial dysrhythmias and, 374 in cardiovascular disease, 190

Calcium hydroxyapatite (HA), 78–80 Calcium oxalate (CaOx), 78–80 Calcium pyrophosphate (CPPD), 78–80 Calymmatobacterium granulomatis

infection, 256

Campylobacter infection

Guillain-Barré syndrome and, 421 infectious diarrhea and, 102, 103, 104 reactive arthritis and, 75

Cancer. See specific cancers

Cancer screening, 1–3

Candida esophagitis, 89 Candidiasis, of skin, 440 Caplan syndrome, 349

Capsaicin cream, 78

Capsule endoscopy, 461

Captopril, for congestive heart failure, 155



USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.

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Carbamazepine

in seizure and epilepsy management, 414–415

in trigeminal neuralgia therapy, 420 Carbapenems, 228

Carbidopa/levodopa, 430

Carbohydrate metabolism, disorders and, 40–48

Carbon monoxide (CO) poisoning, 380–381

burn injuries and, 396

Carbon monoxide diffusing capacity (DLCo), 322, 324

Carboxyhemoglobin (COHb) levels in burn injuries, 397

in carbon monoxide poisoning, 380, 381

Carbuncles, 442

Carcinoid syndrome, 107 Cardiac biomarkers, in chest pain

evaluation, 127

Cardiac catheterization, in IHD, 136 Cardiac enzyme serum levels, in chest pain

evaluation, 127–128

Cardiac glycosides, 156–157 Cardiac output

oxygen delivery and, 326 in shock syndromes, 191

Cardiac resuscitation, in cardiac dysrhythmias, 364–375. See also Cardiopulmonary resuscitation (CPR)

Cardiac tamponade, 173–174 Cardiac troponins, in chest pain

evaluation, 127–128

Cardiogenic shock, 190, 191 Cardiology

acute coronary syndrome, 137–149 arrhythmias, 176–187

chest pain evaluation, 125–128.

See also Angina congestive heart failure, 150–159 ischemic heart disease, 130–137 myocardial disease, 168–171 non-ST elevation myocardial

infarction, 137, 138–140 nonatherosclerotic coronary

syndrome, 148–149

patient history, 125–126

pericardial disease, 172–175

rate and rhythm disturbances, 176–187 shock syndromes, 190–191


ST elevation myocardial infarction, 140–146

valvular heart disease, 160–167 Cardiomyopathy

dilated (congestive), 158, 168–169

hypertrophic obstructive, 169–171 morphologic and hemodynamic

characteristics, 168

restrictive, 171 Cardiopulmonary arrest, pulseless,

management algorithm for, 187, 363

Cardiopulmonary resuscitation (CPR) in ACLS management algorithm,

187, 363

in asystole, 364

in basic life support, 361–363 in children, 362

protocols for, 361–363

in pulseless electrical activity, 368–369 Cardiovascular disease

as chest pain cause, differential diagnosis, 129

diabetes mellitus and, 45 drug therapies for, 188–190 hypercalcemia and, 34

hypertension and, 312, 315 Cardioversion therapy

in atrial dysrhythmias, 373 in atrial fibrillation, 182

in ventricular fibrillation, 365 in ventricular tachycardia, 368

Carditis, 263–270

infective endocarditis, 263–270

myocarditis, 129, 130, 271 Caregivers, of dementia patients, 428 Carotid angioplasty, 411

Carotid endarterectomy, 411 Carotid sinus massage, for atrial

dysrhythmias, 371

Carpal tunnel syndrome, in acromegaly, 16 Caspofungin, 280

Casts, in renal disease diagnosis, 298 Cat bites, 402–403

Cataracts, 470

Catecholamines, in pheochromocytoma, 56, 57

Cathartics, in toxic ingestion/overdose management, 377

Catheter ablation, in atrial fibrillation, 183


Caustics/corrosives, toxic exposure to, 381–382

CD4 cell count, in AIDS, 275–276 CD19, chronic lymphocytic leukemia

and, 211

CD55/CD59, paroxysmal nocturnal hemoglobinuria and, 207

Cefotaxime, 119

Ceftaroline, 227

Ceftriaxone, 119, 227

Celiac disease, 109

antibodies in, 108

Celiac sprue, 109 Cellulitis

periorbital, 471

of skin, 442

Central-acting sympatholytics, as antihypertensives, 317

Central diabetes insipidus (CDI), 19–21, 303

Central nervous system (CNS) infections, 228–233

lymphoma, 217

in salicylate toxicity, 386

Central retinal artery/vein occlusion, 468 Central sleep apnea, 358

Central venous lines, positioning for chest x-rays, 458

Central vertigo, 416 Cephalosporins

gram-negative bacilli and, 227 gram-positive cocci and, 226

Cerebral abscess, 232–233 Cerebral artery occlusion, 409–411 Cerebral contusion, 391, 393

Cerebrospinal fluid (CSF) analysis/culture in meningitis, 230

in multiple sclerosis, 425 Cerebrovascular accident (CVA), 409–411.

See also Stroke Cerebrovascular disease

cerebrovascular accident, 409–411

hypertension and, 313 Cervical cancer, screening for, 2

CHADS2/CHADS2-VASc score, in atrial dysrhythmias, 183, 372

Chancre, in syphilis, 253, 254

Chancroid, 254–255 Charcoal therapy

in acetaminophen toxicity, 379 contraindicated, 380



USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.


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in digoxin toxicity, 387 in salicylate toxicity, 386

in toxic ingestion/overdose

management, 377

Chelation therapy, in lead poisoning, 384 Chemical stress testing, 135

Chest pain. See also Angina causes, 128–130

evaluation, 126–128

patient history and, 125–126 physical examination in, 126–127 quality, 126

testing in, 127–128

Chest physiotherapy, 343

Chest radiography. See Chest X-rays Chest tubes, positioning for chest x-rays,

458

Chest x-rays, 455–459

in adult respiratory distress syndrome, 357

air under diaphragm on, 458–459 in aortic regurgitation, 167

in asbestosis, 349

in asthma diagnosis, 336 basic principles of, 455–456

in burn injury assessment, 397 in chest pain evaluation, 128

in coal miner’s lung/coal worker’s pneumoconiosis, 349

common disorders seen on, 457–459 in congestive heart failure diagnosis, 154 in COPD, 342, 457

decubitus films, 456

expiratory films, 456 film quality of, 456

in heart failure diagnosis, 154 interstitial infiltrates, 327

lateral, 456

in lung cancer, 359

in mitral regurgitation, 161 in mitral stenosis, 161

in pleural effusion, 330, 331–332

in pleural effusion diagnosis, 331–332 in pneumoconiosis, 348

positioning lines and tubes for, 458 in pulmonary disease, 327–332

in pulmonary edema, 159 pulmonary nodule on, 328

in pulmonary thromboembolism, 352–353

in sarcoidosis, 347

in silicosis, 349


Chickenpox, 444 Children, CPR for, 362

Chlamydia psittaci, as pneumonia predisposition, 239

Chlamydia trachomatis lymphogranuloma venereum and, 255 urethritis and, 251–252

Chloroquine, 4

Cholangitis, primary sclerosis, 122 Cholesterol level

in diabetes mellitus, 45 in IHD, 131, 136

Chondroitin sulfate, osteoarthritis and, 78 Chorea, in Huntington disease, 428 Choreoathetoid movements, in Wilson

disease, 123 Chronic disease

anemia of, 196–197, 199

bronchitis, 237

diarrhea, 104–105

hepatitis, 123–124

Chronic hypouricemic gout, 79 Chronic leukemia, 210–213

lymphocytic, 211–212

myelogenous, 210–211

Chronic obstructive pulmonary disease (COPD), 339–343

chest x-rays in, 457 complications, 340

etiology/pathogenesis, 339–340

exacerbations, managing, 342–343 finger clubbing in, 340

physical examination/diagnosis, 340 pleural effusions in, 330–331 prognosis, 343

therapeutic approaches in, 341–343 Chronic pancreatitis, 108

Chronic suppressive therapy, genital herpes, 257

Churg-Strauss syndrome (CS), 82, 292–293

Chvostek sign, 39

Ciguatera-toxin, infectious diarrhea and, 103, 246

Cinacalcet, 37

Cirrhosis, primary biliary, 121 Cirrhosis of liver, 119

gastrointestinal bleeding and, 113, 121

hemochromatosis and, 122 CK-MB isoenzyme, in chest pain

evaluation, 127

Clindamycin, 227, 228


Clopidogrel, in acute coronary syndrome, 145

Closed-angle glaucoma, 469

Clostridial myonecrosis, 262

Clostridium difficile

diarrhea caused by, 105 infectious diarrhea and, 102

Clostridium septicum, 111

Clostridium tetani, 279

Cloxacillin, 225, 226

Clozapine, 428

Cluster headaches, 418

Coagulopathy, 220–224

Coal miner’s lung/coal worker’s pneumoconiosis (CWP), 349

Coarctation of aorta, 316 Cocaine

clearance time, 378

overdose, 382–383 Codeine, clearance time, 378

Cognitive function, dementia and, 426–427 Cold agglutinin hemolytic anemia, 204–206 Colon cancer, 111–113

screening for, 2, 112, 113 Colonoscopy

in colon cancer diagnosis, 112

in diverticular disease diagnosis, 110 as preventive medicine, 2

virtual, 462

Colony-stimulating factors (CSFs), in radiation injury management, 401

Common ALL antigen (CALLA), 209 Community-acquired pneumonia, 241

Complete heart block, 278, 373, 374

Complex seizures, 412 Computed tomography (CT)

in acute pancreatitis, 117–118 central nervous system and, 463 in cerebral abscess, 232

in cerebral artery occlusion, 409, 410 contrast agents for. See Contrast

agents, acute renal failure and

in head trauma, 392–394

high-resolution, of lung parenchyma, 459

in pulmonary embolism, 353–354

in subarachnoid hemorrhage, 395–396 COMT inhibitors, as Parkinson disease

therapy, 430

Concussion, 391, 392



USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.

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Conduction abnormalities, in acute coronary syndrome, 146

Congenital adrenal hyperplasia (CAH), 52–53

Congestive heart failure (CHF), 150–159 case examples, 150

chest x-rays in, 458 diagnosis, 154

inter-related cycles in, 151 management, 154–158

patient workup recommendations, 153 pleural effusions and, 329 precipitating factors in, 152

pulmonary edema in, 151, 153, 158–159

severity classification, 153

signs and symptoms, 152, 153

Conjunctival diseaes, 470–471

Conjunctivitis, 470

Conn syndrome, 316 Consciousness, loss of. See Syncope Constipation, 111

Constrictive pericarditis, 174–175

Contact dermatitis, 435, 452 Continuous positive airway pressure

(CPAP), 333, 334, 402

Contractility increase/reduction, in HOCM, 170

Contrast agents, acute renal failure and, 289 prevention, 290

Cooley anemia, 199

Cooling, rapid, as heat stroke therapy, 398 Coombs test

in autoimmune, cold agglutinin, and drug-induced hemolytic anemia diagnosis, 205

in hereditary spherocytosis diagnosis, 206

Copper, Wilson disease and, 122–123 Coronary angiography, in unstable angina/

NSTEMI, 140

Coronary artery bypass graft (CABG) in ischemic heart disease, 136–137 in STEMI, 144

Coronary atherosclerosis, myocardial infarction without, 149

Coronary heart disease. See Ischemic heart disease (IHD)

Corticosteroids

for asthma, 336–337

for COPD, 341–343

for meningitis, 231

for SLE, 69


Corticotropin-releasing hormone (CRH), 49–51

Costochondritis, as chest pain cause, 129 Cough, nocturnal, 335

Coumadin. See Warfarin Cowden syndrome, 113

Coxiella burnetti, 239, 242 Creatine kinase (CK), in chest pain

evaluation, 127

Creatinine clearance, in acute renal failure, 282

Crepitus, necrotizing fasciitis and, 443 CREST syndrome (limited scleroderma),

71–72

Creutzfeldt-Jakob disease (CJD), dementia secondary to, 427

Crohn disease (CD), 100–101 enteropathic arthropathy in, 76 hyperoxaluria with, 288

kidney stones with, 288

primary sclerosis cholangitis and, 122 Cromolyn sodium, 337

Cryoglobulinemia, 294–295 Cryptococcosis, in AIDS, 275 Cryptosporidia, infectious diarrhea and,

103, 104

Crystal-induced arthropathies, 78–80 Crystals, acute renal failure and, 288 Cullen sign, 117

Cushing disease/syndrome, 49–51 secondary hypertension in, 316

Cyclooxygenase 2 (COX-2) inhibitors in osteoarthritis, 78

in peptic ulcer disease, 76 in RA management, 66

Cyclophosphamides, 425

for nephrotic syndrome, 297 Cyclosporine, acute renal failure and,

289, 290

Cystinuria, 310

Cystitis, 298

Cysts, renal, 311

Cytokines, rheumatoid arthritis and, 65 Cytomegalovirus infection, in AIDS, 274 Cytotoxic drugs, for SLE, 69


D

D-dimer test, 354

Dabigatran, 372

Dalfampridine, 426

Daptomycin, 227


Dawn phenomenon, 47

de Quervain (subacute) thyroiditis, 30 Decay accelerating factor (DAF), 206, 207 Decompensated heart failure, 152 Decubitus film, chest x-ray, 456 Decubitus (pressure) ulcers, 453

Deep vein thrombosis (DVT). See also

Pulmonary embolism (PE) leg swelling in, 351

limited distal, 356

overview, 350

pulmonary thromboembolism and, 350–357

risk categories for, 351–352 Defibrillation, 365

Degenerative joint disease (DJD), joint aspiration in, 63

Delirium tremens (DT), 390 Demand ischemia, 133

Dementia, 426–428 Depression

acute coronary syndrome and, 147 Parkinsonism and, 430

Dermal-epidermal junction,

cellulitis and, 442 Dermatitis

atopic, 451–452

contact, 435, 452

papulosquamous, 451–453

seborrheic, 452

stasis, 452

Dermatitis herpetiformis, 108

Dermatographism, 435 Dermatology

acne, 454

bacterial infections, 441–443

benign/precancerous lesions, 447–448

bullous/blistering diseases, 434–435

decubitus ulcers, 453

drug eruptions/hypersensitivity, 435–438

fungal infections, 439–440

hair-related disorders, 453

malignant diseases, 448–450

parasitic infections, 445–446 scaling disorders/papulosquamous

dermatitis, 451–453 skin anatomy and, 433

toxin-mediated diseases, 446–447

viral infections, 443–445



USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.


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Dermatomyositis, 83–84

Dermatophyte infections, 439, 440

Dermo-epidermal junction, 434 Dermopathy, in Graves’ disease, 26 Desensitization, urticaria and, 436 Desmopressin (DDAVP)

in hemophilia, 220

in von Willebrand disease, 219 Detachment, retinal, 466–467

DEXA scan, in osteoporosis screening, 8 Dexamethasone therapy, for meningitis, 231 Dextrose therapy, in toxic ingestion/

overdose management, 377 Diabetes insipidus

central and nephrogenic, 19–21, 303

hypernatremia and, 303

Diabetes mellitus, 40–47 Candida esophagitis in, 89 classification, 40

complications, 43–47

end-stage renal disease and, 298 glomerulonephritis and, 291, 295 as IHD risk factor, 132

screening for, 9

Diabetic ketoacidosis (DKA), 43–44 Diabetic nephropathy, 45–46

Diabetic neuropathy, 46–47

Diabetic retinopathy, 46, 465–466 Dialysis

for alcohol intoxication, 380

in end-stage renal disease, 298–300 for lithium poisoning, 386

for salicylate toxicity, 387 in toxic ingestion/overdose

management, 377 Diaphragm, air under, on chest x-rays,

458–459

Diarrhea

antibiotic-associated, 105–106 carcinoid syndrome and, 107 chronic, 104–105

infectious, 102–105, 246–248

irritable bowel syndrome and, 106–107 lactose intolerance and, 106

nocturnal, 105

traveler’s, 4, 104 Diastolic dysfunction

in congestive heart failure, 151, 158

in HOCM, 169

Dicloxacillin, 225, 226

Diet. See Lifestyle modification


Diffuse capillary leak, burn injuries and, 397 Diffuse esophageal spasm, 88

Digitalis

for congestive heart failure, 156–157 toxic effects, 157

Digoxin

drug interactions associated with, 157 toxicity, 387

Dilated (congestive) cardiomyopathy, 168–169

therapy for, 158, 169

Dipeptidyl peptidase (DPP-IV) inhibitors, for diabetes mellitus, 42

Diphtheria/tetanus (DT) vaccine, 5 Dipyridamole stress test, 135 Discoid lupus (DLE), 69

Disease-modifying agents in dementia, 428

in multiple sclerosis, 425

in rheumatoid arthritis, 67–68 Disopyramide, adverse effects, 189 Disseminated intravascular coagulation

(DIC), 221–222

acute leukemia and, 209 liver disease and, 119

Distal renal tubular acidosis, 308–309 Distributive shock, 190, 191

Diuresis. See Urine output Diuretics

as antihypertensive, 316

for congestive heart failure, 155–156 lithium poisoning and, 385

in toxic ingestion/overdose

management, 377

Diverticulitis, 110–111

Diverticulosis, 110

Dizziness, 415–417

DMARD (disease-modifying anti- rheumatic drugs), 67–68

adverse effects, 67 Dobutamine stress test, 135 Dog bites, 402–403

Domestic violence, screening for, 10 Dopamine

hyperprolactinemia and, 15

Parkinsonism and, 430

Doppler echocardiography, in mitral valve prolapse, 164

Doppler ultrasound, in pulmonary embolism diagnosis, 354

Doxycycline, 104, 228


DPP-IV (dipeptidyl peptidase) inhibitors, 42 Dressler syndrome, 147

Drowning, 401–402

Drug abuse, overdose/toxicity

management in, 382–384

Drug-induced hemolytic anemia, 204–205 Drug-induced lupus erythematosus, 70 Drug reactions, dermatological, 435–438

erythema multiforme, 436–437

erythema nodosum, 438 fixed drug reaction, 438 morbilliform rashes, 436

Stevens-Johnson syndrome, 437 toxic epidermal necrolysis, 437–438 urticaria, 435–436

Drug therapies. See also specific drugs and therapeutic agents

for acute coronary syndrome, 144–145 acute renal failure caused by, 289–290 antihypertensives, 316–318

for asthma, 336–337

for cardiovascular disease, 188–190 for congestive heart failure, 154–158 for hypertension, 316–318

Dry drowning, 401

DUMBELSS syndrome, 389

Dumping syndrome, 99

Dyesthesia, in Guillain-Barré syndrome, 421 Dyslipidemia, in diabetes mellitus, 45 Dyspepsia, nonulcer, 99

Dysphagia, oropharyngeal vs. esophageal, 85 Dysplastic nevus, 448

Dyspnea, cardiac vs. pulmonary, 154 Dysrhythmias. See also Arrhythmias in acute coronary syndrome, 146

asystole, 364

atrial, 369–372

ischemia-related, 361, 364, 365, 367, 369

management of, 364–375

pulseless electrical activity, 368–369

in tricyclic antidepressant toxicity, 388 ventricular, 365–368


E

Eaton-Lambert myasthenic syndrome, 422 Echocardiography

in aortic regurgitation, 167

in congestive heart failure, 154 in ischemic heart disease, 136 in mitral regurgitation, 163

in mitral stenosis, 161



USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.

480

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Index



Eczema, 451–453 Edema

pitting, in congestive heart failure, 153 pulmonary. See Pulmonary edema

Edrophonium (Tensilon) test, 422 Efavirenz, 278

Effusion

parapneumonic, 330

pericardial, 173–174 pleural. See Pleural effusion

Electrocardiogram (ECG)

in acute pericarditis, 172–173 in aortic regurgitation, 167 in asystole, 364

in atrial fibrillation, 179, 371

in atrial flutter, 179, 370 in atrial tachycardia, 370

in chest pain evaluation, 127 in complete heart block, 374

in congestive heart disease, 154

in congestive heart failure diagnosis, 154 in digoxin toxicity, 387

in first-degree heart block, 374 in hypothermia, 399

in ischemic heart disease, 134 in mitral regurgitation, 163 in mitral stenosis, 161

in myocardial infraction, 127 normal sinus rhythm on, 370 in NSTEMI, 142

in pulmonary edema, 159

in pulmonary thromboembolism, 353 in pulseless electrical activity, 368

in second-degree heart block, 177, 374

in STEMI, 141–142

in third-degree heart block, 178 in torsade de Pointes, 186, 367 in ventricular fibrillation, 365

in ventricular tachycardia, 367–368 Electroencephalogram (EEG), 413, 415 Electrolytes

changes in hypopituitarism, 18 in digoxin toxicity, 387

Electromyography (EMG), 422 Embolism, pulmonary. See Pulmonary

embolism (PE) Emergency, hypertensive, 315 Emergency medicine

anaphylaxis, 402

basic life support, 361–363 burn injuries, 396–398


drowning, 401–402

head trauma, 391–394

heat disorders, 398–399

radiation injuries, 400–401

subarachnoid hemorrhage, 394–396 toxicology, 376–391. See also Toxicology venomous bites and stings, 402–404

Emphysema, chest x-rays in, 457 Empty sella syndrome (ESS), 18–19

Enalapril, for congestive heart failure, 155 Encainide, adverse effects, 189 Encephalitis, 231–232

Encephalopathy, Wernicke, 390, 391 End-stage renal disease, 281

dialysis in, 298–300

Endarterectomy, 411

for cerebrovascular accident, 411 Endocarditis

acute, embolic features of, 269 colon cancer and, 111

infective. See Infective endocarditis Libman-Sacks, 69

Endocrinology

adrenal gland diseases, 48–57 carbohydrate metabolism disorders,

40–48

parathyroid gland diseases, 33–39 pituitary gland diseases, 11–23 posterior pituitary lobe diseases, 19–23 testicular hypogonadism, 57–58 thyroid gland diseases, 23–33

Endoscopic retrograde

cholangiopancreatography (ERCP)

in acute pancreatitis, 116, 117

described, 461

Endoscopic ultrasound, 460 Endoscopy

capsule, 461

in epigastric pain evaluation, 92

in gastroesophageal reflux disease, 93 in gastrointestinal bleeding evaluation,

116, 117

in inflammatory bowel disease diagnosis, 100

Endotracheal tubes, positioning for chest x-rays, 458

Entecavir, for hepatitis infection, 250 Enteropathic arthropathy, 74, 76

Eosinophilic esophagitis, 90

Epidural hematoma, 391, 393


Epigastric pain, 93–99

in Barrett esophagus, 94 in dumping syndrome, 99 in gastritis, 96–97

in gastroesophageal reflux disease, 93–94

in gastroparesis, 98

in nonulcer dyspepsia, 99 overview, 92

in peptic ulcer disease, 94–96

in Zollinger-Ellison syndrome, 97–98 Epilepsy, 411–415

Erectile dysfunction (ED)

acute coronary syndrome and, 148 in diabetes mellitus, 47

Erysipelas, 442

Erythema migrans rash (Lyme disease), 270–271

Erythema multiforme, 436–437 Erythema multiforme major, 437 Erythema nodosum (EN)

drug-induced, 438

in rheumatic disorders, 76 Erythrocyte sedimentation test (ESR), in

temporal arteritis, 83

Erythrocytosis, 340

Escherichia coli, infectious diarrhea and, 103, 104

Esophageal dysfunction, in CREST syndrome, 71

Esophageal dysphagia, 85

Esophageal varices, 114

Esophagitis, 89–90

Esophagogastroduodenoscopy (EGD), 93 Esophagus, diseases of, 85–91

achalasia, 86–87

cancer, 87–88

esophagitis, 89–90

Mallory-Weiss syndrome, 91

overview, 85

rings and webs, 89

Zenker diverticulum, 90–91

Essential hypertension, 312–313

Essential thrombocythemia, 213 Essential tremor

benign, 431

Parkinsonism vs, 430

Etanercept (Enbrel), 67

Ethambutol (ETB), 79, 244, 274

Ethanol-induced hypoglycemia, 48 Ethical issues, in ALS therapy, 423–424



USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.


481

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Ethosuximide, 414

Ethylene glycol poisoning, 379–380 acute renal failure and, 288

Euvolemic states

in hyponatremia, 302

rate control in atrial dysrhythmias and, 372

Exchange transfusion, in sickle cell disease, 204

Exercise

asthma induced by, 335

lack of, as IHD risk factor, 132 Exercise stress test

in acute coronary syndrome, 146 in ischemic heart disease, 134–135

Exertional heat disorders, 398 Exophthalmus, 26

Expiratory film, chest x-ray, 456 Extracellular fluid (ECF), hyponatremia

and, 301

Extrinsic (allergic, atopic) asthma, 335 Exudative pleural effusion, 329


F

Factitious hyperinsulinism, 48

Factitious hyperthyroidism, 25

Factor VIII, 119

False-positive stress tests, 135 Familial adenomatous polyposis, 112 Familial hypocalciuric hypercalcemia

(FHH), 34

Faruncles, 442

Fasciitis, necrotizing, 442–443

Fasting hypoglycemia, 47

Fat embolism, 357

Feedback inhibition, pituitary gland and, 12 Fibrillation

atrial. See Atrial fibrillation (A-fib) ventricular, 365

Fibrinolytics. See Thrombolytics Fidaxomicin, 106

Finger clubbing, in chronic hypoxemia, 340 Fingolimod, 426

First-degree AV block, 176, 373, 374

First-degree burns, 397

Fistula, perilymphatic, 416 Fixed drug reaction, 438 Flecainide, adverse effects, 189 Flow volume loops, 325–326 Fluconazole, for esophagitis, 89


Fluid/electrolyte disorders hyperkalemia, 304–305

hypernatremia, 303

hypokalemia, 304

hyponatremia, 300–302

renal disease, 300–305

SIADH, 302–303

Fluid resuscitation/replacement, in burn injury, 397

Fluorescent antinuclear antibody (FANA) test, 63

Fluoroquinolones, 227

Focal-segmental glomerulosclerosis (FSGS), 297

Folic acid deficiency, 201

Follicle-stimulating hormone (FSH) hyperprolactinemia and, 14

hypopituitarism and, 17 Follicular carcinoma, of thyroid, 32 Folliculitis, 442

Food poisoning, 246–248 Foot ulcer, diabetic, 46

Forced diuresis, in toxic ingestion/ overdose management, 377

Forced expiratory volumes (FEVs) as COPD prognostic factor, 343

in pulmonary function testing, 323

Francisella tularensis, as pneumonia predisposition, 239

Freshwater drowning, 401

Frontotemporal dementia, 427

Fungal infections, 279–280

of skin, 439–440

Furuncles, 442


G

Gait, in Huntington disease, 428 Galactorrhea, in hyperprolactinemia, 14 Gallbladder, HIDA scanning of, 461–462 Gallbladder disease, as chest pain cause, 129 Gallstone pancreatitis, 116, 117

Gamma glutamyl transpeptidase (GGTP), 121

Gangrene, gas, 262

Gardner syndrome, 113

Gas chromatography/mass spectrometry, in toxicology screen, 378

Gas exchange disturbances, 326–327 in asthma, 335–336

Gas gangrene, 262


Gastric lavage

in hypothermia management, 399 in toxic ingestion/overdose

management, 377, 382, 385 Gastrin-producing cells, cancer of. See

Zollinger-Ellison syndrome

(ZES)

Gastrinomas. See Zollinger-Ellison syndrome (ZES)

Gastritis, 96–97 Gastroenterology

acute pancreatitis, 116–118

colon cancer, 111–113

constipation, 111

diarrhea, 102–107

diverticular disease, 110–111 epigastric pain, 92–99. See also

Epigastric pain

esophageal disease, 85–91

gastrointestinal bleeding, 113–116 inflammatory bowel disease, 100–101 liver disease and cirrhosis, 119–123 malabsorption syndromes, 108–109 peptic ulcer disease, 94–96

Gastroesophageal reflux disease (GERD), 93–94

Barrett esophagus and, 94 as chest pain cause, 129

esophageal eosinophilia and, 90 Gastrointestinal bleeding, 113–116 Gastrointestinal tract

disorders of, chest pain and, 130 hypercalcemia and, 34

infection of, 246–248 radiation injury to, 400

Gastroparesis, 98

in diabetes mellitus, 46–47 Generalized seizures, 412

Genital infections, 251–257

chancroid, 254–255

granuloma inguinale, 256

herpes virus, 257

lymphogranuloma venereum, 255–256 primary chancre of syphilis, 253

warts, 257

Giant cell arteritis. See Temporal arteritis Giant cells, multinucleated, 443

Giardia, infectious diarrhea and, 103, 104

Glatiramer acetate therapy, 425, 426

Glaucoma, 469–470



USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.

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Index



Glomerular filtration rate (GFR), 281, 282–288

Glomerulonephritis (GN), 291

causes, 291, 292

disease spectrum in, 291–297. See also specific diseases

Glucagon-like peptide (GLP), 42 Glucocorticoids

in multiple sclerosis, 425

in myasthenia gravis therapy, 422 in RA management, 67

Glucosamine, osteoarthritis and, 78 Glucose-6-phosphate dehydrogenase

(G6PD) deficiency, 207–208 Glucose tolerance, in acromegaly, 16 Glycoprotein IIb/IIIa inhibitors

for STEMI, 145

for unstable angina/NSTEMI, 140

Glycosylated hemoglobin A1c, 41 Goiter

in thyroiditis, 31

toxic diffuse (Graves’ disease), 25, 26–28 toxic multinodular (Plummer disease),

25

Gonads, radiation injury to, 400 Gonorrhea, septic arthritis and, 261–262 Goodpasture syndrome (GP), 291, 292,

293, 324, 357

Gottron’s papules, 84

Gout, 78–80

chronic hypouricemic, 79 joint aspiration in, 62–63

Gram-negative bacilli, antibiotics for, 227–228

Gram-positive cocci, antibiotics for, 225–227 Gram stain, joint aspiration and, 62 Grand mal (tonic-clonic) seizures, 412 Granuloma inguinale, 256

Graves’ disease, 25, 26–28

Greenfield filter, 356

Griseofulvin, 439 Growth hormone (GH)

acromegaly and, 15–16

hypopituitarism and, 18

Guillain-Barré syndrome (GBS), 420–421 Gumma, in syphilis, 253

Gynecomastia, 58


H

Haemophilus ducreyi, 254

Haemophilus influenzae, 239


Hair-related disorders, 453 Hairy cell leukemia (HCL), 211 Hallucinogen overdose, 383

Hallucinosis, alcoholic, 390

Haloperidol, 428

Hampton hump, 353

Hashimoto disease/thyroiditis, 17, 25, 28,

30, 31

Head

infections, 233–236

trauma to, 391–394

Headache, 417–419

brain abscess and, 232

in carbon monoxide poisoning, 380, 381 Heart failure (HF). See also Congestive

heart failure (CHF)

in acromegaly, 17

compensatory mechanisms during, 151 decompensated, 152

with preserved ejection fraction, 151 systolic. See Systolic dysfunction, in

congestive heart failure

Heart sounds, abnormal, chest pain syndromes and, 126

Heat cramps, 398

Heat disorders, 398–399

Heat exhaustion, 398

Heat stroke, 398

Heavy metals toxicity, 384

Heerfordt-Waldenstrom syndrome, 347

Helicobacter pylori epigastric pain and, 92 gastritis and, 96–97

peptic ulcer disease and, 95, 96

Hematemesis, 113 Hematology

acute leukemia, 209–210

anemia, 193–195

aplastic anemia, 208–209

chronic leukemia, 210–213

coagulopathy, 220–224

hemolytic anemia, 201–208

lymphoma, 214–217

macrocytic anemia, 200–201

microcytic anemia, 196–199 plasma cell disorders, 213–214 platelet disorders, 218–219

Hematomas, in head trauma, 391–394 epidural, 393

subdural, 392, 393, 394


Hematuria

microscopic, in sickle cell disease, 203 in renal disease diagnosis, 298

Hemochromatosis, 122

Hemodynamic instability, in ventricular tachycardia, 368

Hemoglobin

acute renal failure and, 287–288 oxygen delivery and, 326

Hemolytic anemia, 201–208. See also specific forms

Hemolytic uremic syndrome (HUS), 222–223

Hemophilia A and B, 220 Hemorrhage

retinal, 468

subarachnoid. See Subarachnoid hemorrhage (SAH)

subconjunctival, 471 Hemorrhagic pleural effusions, 330 Hemosiderinuria, 207

Henoch-Schönlein purpura, 292, 294 Heparin, for pulmonary

thromboembolism, 355 Heparin-induced thrombocytopenia and

thrombosis (HITT), 223 Heparin-induced thrombocytopenia

(HIT), 223

in pulmonary thromboembolism, 355 Hepatitis

acute, 248–251

chronic, 123–124 comparative features in, 249

Hepatitis A virus

acute infection, 248–251

vaccine, 3, 6 Hepatitis B virus

acute infection, 248–251

chronic infection, 248 liver disease and, 123–124 needlestick injury, 251

in polyarteritis nodosa, 82 vaccine for, 3, 5

Hepatitis C virus

acute infection, 248–251

chronic infection, 248 liver disease and, 123–124

Hepatitis D virus, 248–251 Hepatitis E virus, 248–251 Hepatitis G virus, 248–251 Hepatorenal syndrome, 283



USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.


483

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USMLE Step 2 CK l Internal Medicine



Hereditary cystic disease, 311 Hereditary nonpolyposis syndrome, 112

Hereditary polyposis syndromes, 112–113 Hereditary spherocytosis, 206

Heredity, as IHD risk factor, 133 Herniation

hiatal, as chest pain cause, 129

spinal cord compression and, 405–406 Heroin, clearance time, 378

Herpes, genital, 257 Herpes simplex infection

keratitis, 471

of skin, 443–444

Herpes zoster/varicella infection, 444 vaccine, 7

Hiatal hernia, as chest pain cause, 129 HIDA scanning, 461–462

High-resolution computed tomography, of lung parenchyma, 459

Highly active antiretroviral therapy (HAART), 278

Histamine blockers

in gastroesophageal reflux disease, 94 in peptic ulcer disease, 75

in Zollinger-Ellison syndrome, 98

Histoplasma capsulatum, as pneumonia predisposition, 239

Hives, in urticaria, 435 Hodgkin disease, 214–216

adverse prognostic factors in, 215 staging in, 215

Home oxygen therapy, for COPD, 341 “Honeymoon” period, in IDDM, 47 Horner syndrome, 410

Hospital-acquired pneumonia, 242 Hospitalization

asthma patients, 337–338 discharge recommendations,

in ACS, 145

for persistent hypoxemia, 332 “H’s and T’s” of dysrhythmia

management, 364

Human bites, 403

Human immunodeficiency virus (HIV).

See also Acquired immune deficiency syndrome (AIDS)

Candida esophagitis and, 89 management in pregnant patients, 278 rheumatoid arthritis and, 65

Human papillomavirus (HPV) genital warts caused by, 257 vaccine for, 7


Huntingtin protein, 428

Huntington disease, 428–429 Hyaluronic acid, for osteoarthritis, 78

Hydralazine, for congestive heart failure, 155 Hydrocephalus, normal pressure, 427 Hydromorphone, clearance time, 378 Hydroxychloroquine, in RA management, 67 Hydroxyurea, in sickle cell disease, 204 Hyperaldosteronism

amiodarone-induced, 29 secondary hypertension in, 316

Hypercalcemia, 33–35

acute renal failure and, 288 MEN-1 and, 97

Hypercalciuria, 310

Hypercarbia, in drowning victims, 401 Hypercholesterolemia, screening for, 9 Hyperinsulinism, 47

factitious, insuloma vs., 48 Hyperkalemia, 304–305

in renal tubular acidosis, 309 Hyperlipidemia, management in IHD, 136 Hypermagnesemia, in end-stage renal

disease, 299

Hypernatremia, 303

Hyperosmolar nonketotic coma (HONK), 45

Hyperoxaluria, 310

Crohn disease and, 288 Hyperparathyroidism

primary, 33, 36–37, 38

secondary, 38

tertiary, 38

Hyperphosphatemia, in end-stage renal disease, 299

Hyperpigmentation, in Addison disease, 54 Hyperprolactinemia, 13–15 Hypersensitivity, dermatological disease

and, 435–438

Hypertension (HTN)

in end-stage renal disease, 298, 299

essential, 312–313

glomerulonephritis and, 291 as IHD risk factor, 132 malignant, 314

medications for treating, 316–318 portal, in liver disease, 119 resistant, 315

screening for, 9, 315

secondary, 313, 315–316

Hypertensive emergency, 312, 315


Hyperthyroidism (thyrotoxicosis), 25–28, 30

Hypertonicity, in diabetes insipidus, 20 Hypertrophic obstructive cardiomyopathy

(HOCM), 169–171

in aortic stenosis differential diagnosis, 165

effect of maneuvers in, 166 morphologic and hemodynamic

characteristics, 168 Hypervolemic states, in hyponatremia, 301 Hypoaldosteronism, 309–310

Hypocalcemia, 38

in end-stage renal disease, 299 Hypocitraturia, 310

Hypoglycemia, 47–48

carbon monoxide poisoning vs., 381 Hypogonadism, 57–58

Hypokalemia, 304

digoxin poisoning and, 387

in vitamin B12 deficiency, 201 Hyponatremia, 300–302

Hypoparathyroidism, 38–39

Hypopituitarism, 17–18 Hyporeninemic renal tubular acidosis,

309–310

Hypothalamic-pituitary axis (HPA), pituitary gland diseases and, 11–12

Hypothalamus, 11–12

Hypothermia, 399–400

in drowning victims, 401 therapeutic, post-resuscitation care

and, 365

Hypothyroidism, 28–30

Hypouricemic therapy, 79 Hypoventilation

renal acidosis and, 308 respiratory acidosis and, 308

Hypovolemic shock, 191

Hypovolemic states, in hyponatremia, 301 Hypoxemia

chronic, finger clubbing in, 340

in COPD, home oxygen therapy for, 341 persistent, hospital admissions and, 332

Hypoxia, in drowning victims, 401


I

I STUMBLE (mnemonic), hemodialysis and, 377

Ice water immersion

as heat stroke therapy, 398

for supraventricular tachycardia, 371



USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.

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Idiopathic pulmonary fibrosis (IPF), 346 Idiopathic rapidly progressive

glomerulonephritis (RPGN), 295–296

Idiosyncratic asthma, 335

Imaging studies. See specific imaging modalities

Imatinib, 210–211

Immune system, monitoring in AIDS, 276–277

Immune thrombocytopenic purpura (ITP), 218

Immunizations, 4–7. See also Vaccines Immunoglobulin A (IgA)

anti-tissue transglutaminase antibody, 108, 109

nephropathy, 294

Immunoglobulin E (IgE) mediation, in urticaria, 435

Immunoglobulin therapy

in Guillain-Barré syndrome, 422 in myasthenia gravis, 422

Impetigo, 441

Implantable cardioverter/defibrillator (AICD), 158

Inclusion body myositis, 83–84 Incretin mimetics, 41–42

Indapamide, in congestive heart failure, 156 Indinavir, acute renal failure and, 290 Induced vomiting, in toxic ingestion/

overdose management, 377

Infectious diarrhea, 102–105, 246–248 Infectious disease

acquired immunodeficiency syndrome, 273–278

antibiotics for, 225–228

aspergillosis, 279–280

asthma in, 335

of bone and joint, 260–262 carditis, 263–270

of central nervous system, 228–233 diarrhea, 102–105, 246–248

in end-stage renal disease, 299 gastrointestinal, 246–248

genital infections, 251–257

glomerulonephritis (postinfection), 294 Guillain-Barré syndrome and, 421

of head and neck, 233–236

hepatic (acute viral), 248–251. See also

Hepatitis entries

of lung, 237–245


Lyme disease, 270–271

nephrolithiasis and, 311

Q-fever, 239, 242

Rocky Mountain spotted fever, 272 sexually transmitted diseases, 251–257 of skin, 439–446

tetanus, 279

toxoplasmosis, 232, 233, 274–275 urinary tract infections, 258–260

Infective endocarditis, 263–270

acute, 265

bacterial, prevention of, 269–270 complications, 267

diagnostic criteria, 267

embolic features, 269

manifestations, 266–267 microorganisms responsible for, 265 risk factors for, 263–264

subacute, 266

surgical criteria for, 268 treatment for, 267–268

Inflammatory bowel disease (IBD), 100–101 enteropathic arthropathy in, 76 primary sclerosis cholangitis and, 122

Inflammatory diseases, hypopituitarism and, 17

Inflammatory myopathies, 83–84

Infliximab (Remicade), 67

Influenza, 236

carbon monoxide poisoning vs., 381 vaccine for, 5

Injury

to head, 391–394

screening for, 10

to skin, “rule of nines” assessment of, 397 Insulin deficiency/insufficiency, 43–44 Insulin-dependent diabetes mellitus

(IDDM), 40

“honeymoon” period in, 47 Insulin-like growth factor (IGF), in

acromegaly, 16

Insulin therapy, 42

preparations, 43

Insulinoma, 47

Intensive care unit (ICU), persistent hypoxemia and, 332

Interferon gamma release assay (IGRA), 245 Interferons, in multiple sclerosis therapy,

425

International Normalized Ratio (INR), 224 Interstitial lung diseases (ILD), 345–349

chest x-ray, 327


Interstitial syndromes, of lung, 457 Intertriginous infections, 440 Intracranial hemorrhage, headache with,

417

Intrinsic asthma, 335 Intrinsic thyroid autonomy,

hyperthyroidism and, 25

Invasive aspergillosis, 280

Invasive ventilation, 333–334 Iodine therapy

for Graves’ disease, 28 hypothyroidism and, 28 thyroid storm and, 28

Ionizing radiation, injury from, 400 Ipecac, 377

Iron deficiency anemia, 196 in celiac sprue, 108

iron indices in, 199

Iron indices, in microcytic anemias, 199 Iron malabsorption, 108

Irrigation

following caustics/corrosives exposure, 382

whole bowel, in toxic ingestion/ overdose management, 377

Irritable bowel syndrome (IBS), 106–107 Ischemic heart disease (IHD), 130–137

acute coronary syndrome and, 147 risk factors for, 131–133

Isoniazid (INH), for tuberculosis, 244 Isopropyl alcohol ingestion, 380 Isosorbide dinitrate, for congestive heart

failure, 155

Isospora, infectious diarrhea and, 103, 104 Itraconazole, for fungal infections, 439 Ixodes scapularis, 270


J

J-wave, in hypothermia, 399

Janeway lesions, in infective endocarditis, 267

Joints

aspiration, in rheumatologic disease evaluation, 62–63

osteoarthritis and, 77

Jugular venous pressure (JVP), in congestive heart failure, 151, 152

Juvenile polyposis syndrome, 112



USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.


485

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USMLE Step 2 CK l Internal Medicine



K

Kaposi sarcoma, 450

Kartagener syndrome, 344

Kayser-Fleisher rings, in Wilson disease, 122, 123

Keratitis, herpes simplex, 471 Keratoderma blennorrhagica, 76 Keratosis

actinic, 448

seborrheic, 447–448

Kidney. See also Renal function and disease; Renal entries

ACE inhibitor effects on, 283 stones. See Nephrolithiasis transplantation of, 300

Kimmelstiel-Wilson syndrome, 46

Klebsiella, as pneumonia cause, 239, 240

Klinefelter syndrome, 58

Koebner phenomenon, 451

KOH test, 439, 440

Korsakoff psychosis, 390, 391

Kussmaul respiration/sign, 44, 171, 174


L

Labyrinthitis, 416, 417

Lactate dehydrogenase (LDH), in pleural effusion diagnosis, 329

Lactose intolerance, 106

Lamivudine, acute viral hepatitis and, 250 Lamotrigine, for seizures and epilepsy,

414–415

Lanreotide, acromegaly and, 13 Large-cell carcinoma, of lung, 359

Laryngospasm, dry drowning and, 401 Lateral chest x-rays, 456

Lavage. See Bronchoalveolar lavage; Gastric lavage

Lead poisoning, 384 basophilic stippling in, 198

Ledipasvir/sofosbuvir (Harvoni), 124,

250, 251

Leg raising, effect on systolic murmurs, 166 Leg swelling, unilateral, in DVT, 351 Legionella, as pneumonia cause, 239, 240 Lesions, benign vs. malignant, 447 Leukemia

acute, 209–210

chronic, 210–213

Leukemoid reaction, 210

“Leukostasis” syndrome, 209 Leukotriene modifiers, for asthma, 337


Levetiracetam, for seizures and epilepsy, 414, 415

Levothyroxine (T4), 30, 31, 32 Lewy bodies, dementia with, 427

Libman-Sacks endocarditis, 69 Lidocaine

adverse effects, 189

for ventricular tachycardia, 368 Lifestyle modification

in diabetes mellitus, 41, 45

in end-stage renal disease, 299 in GERD management, 94

in hypertension management, 313 Limited distal DVT, 356

Limited scleroderma (CREST syndrome), 57–58

Linezolid, 227

Lipase test, in acute pancreatitis, 117 Lipid management

in diabetes mellitus, 45

for secondary prevention of IHD, 136 Lipid testing, in diabetes mellitus, 45 Lisinopril, for congestive heart failure, 155 Listeria monocytogenes, 229

Lithium/Lithium poisoning, 385–386 acute renal failure and, 290

Liver biopsy, primary sclerosis cholangitis and, 122

Liver disease

acute viral infections, 248–251 alpha-1 antitrypsin deficiency, 123 chronic hepatitis B and C, 123–124 coagulopathy and, 221

hemochromatosis, 122

hepatorenal syndrome, 283 primary biliary cirrhosis, 121 primary sclerosis cholangitis, 122

serum-ascites albumin gradient and, 120 Wilson disease, 122–123

“Locked-in” syndrome, 410

Löfgren syndrome, 347 Loop diuretics

as antihypertensive, 316

in congestive heart failure, 156 Loss of consciousness. See Syncope Low molecular-weight heparin

(LMWH), for pulmonary thromboembolism, 355

Lower esophageal sphincter (LES) achalasia and, 86

in GERD, 93


Lumbar puncture

in meningitis, 230

in subarachnoid hemorrhage, 396 Lung

interstitial diseases of, 327, 345–349 interstitial syndromes of, 457

Lung cancer, 358–360

screening for, 2, 360

Lung infections, 237–245

abscess, 237–238

bronchitis, 237

pneumonia, 238–242

tuberculosis, 243–245

Lung parenchyma, imaging tools for, 459 Lung volumes, in pulmonary function

testing, 321, 322–323

Lupus anticoagulant, 65 Lupus erythematosus

drug-induced, 70

systemic. See Systemic lupus

erythematosus (SLE) Lupus nephritis, 70

Lupus pernio, 347 Luteinizing hormone (LH)

hyperprolactinemia and, 14

hypopituitarism, 17

Lyme disease, 270–271

Lymphocytic thyroiditis, 31

Lymphogranuloma venereum, 255–256

Lymphomas, 214–217

Lynch syndrome, 112


M

Macroadenomas, anterior pituitary, 13 Macrocytic anemia, 200–201

etiology, 193

Macrolides, 227

Macular degeneration, age-related, 467–468

Magnesium therapy, for ventricular fibrillation, 368

Magnetic resonance imaging (MRI) of brain, in multiple sclerosis, 425 central nervous system and, 463

Malabsorption syndromes, 108–109

Malar rash, 62, 69 Malaria, prophylaxis for, 3

Malassezia furfur infection, of skin, 439 Malignant diseases, of skin, 448–450 Malignant hypertension, 314

Malignant hyperthermia, 399



USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.

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Index



Mallory-Weiss syndrome, 91

Maltese cross shape, in urinalysis, 296 Mammography, in breast cancer

screening, 2 Mast cells

activation, in urticaria, 435 stabilizers, for asthma, 337

Mean corpuscular volume (MCV), anemia and, 193–194

Measles, mumps, rubella (MMR) vaccine, 6 Mechanical cardioversion, in atrial

fibrillation, 182 Mediastinoscopy, in lung cancer, 359 Medullary carcinoma, of thyroid, 32 Meglitinides, 42

Melanoma, 448–449

Memantine, 428 Membranoproliferative nephrotic

syndrome, 297

Membranous nephrotic syndrome, 297 Memory loss, head trauma and, 391 Ménière disease, 416

Meningitis, 228–231

Meningococcal vaccine, 4, 6

  1. Mercaptopurine (6MP), for

inflammatory bowel disease, 100 Mesalamine, for inflammatory bowel

disease, 100

Mesangial nephrotic syndrome, 297 Mesothelioma, pleural/peritoneal, 349

Metabolic acidosis, 306–307

Metabolic alkalosis, 305–306 Metacarpophalangeal (MCP) joints,

osteoarthritis in, 122 Metered dose inhalers (MDIs),

for asthma, 336

Metformin (biguanides), 41, 42

Methacholine challenge test, 322, 324 Methadone, clearance time, 378 Methanol poisoning, 379–380

Methicillin-resistant Staphylococcus aureus

(MRSA), 226, 227

hospital-acquired pneumonia and, 238 skin MRSA, antibiotics for, 228

Methimazole, for hyperthyroidism, 27 Methotrexate (MTX), in RA management,

67

Metronidazole, 228

for diarrhea, 105–106 Mexilitine, adverse effects, 189

Microadenomas, of anterior pituitary, 13


Microalbuminuria, 46

Microcytic anemia, 196–199

etiology, 193

iron indices in, 199 lead poisoning and, 384

Middle cerebral artery (MCA) occlusion, 409–410

Migraine headaches, 418

Migratory arthropathy, 61

Mild cognitive impairment, dementia and, 427

Mini Mental Status Examination (MMSE), 427

Minimal change disease, 297 Miosis, 376

Mitoxantrone, 425

Mitral regurgitation, 161–163 acute vs. chronic etiologies, 162

in aortic stenosis differential diagnosis, 165

effect of maneuvers in, 166 Mitral stenosis, 160–161 Mitral valve prolapse, 163–164

Mobitz I & II second-degree AV blocks, 177, 373, 374

Molluscum contagiosum, 444–445

Monkey bites, 403

Monoarticular symmetric involvement, in rheumatoid diseases, 61

Monobactams, 228 Monoclonal antibodies, in RA

management, 67

Monoclonal gammopathy of uncertain significance (MGUS), 214

Mononeuropathy, 46 Monosodium urate (MSU), 78–80 Moraxella, 239

Morbilliform rashes, 436 Morphine, clearance time, 378 Movement disorders, 428–431 Mucosal-associated lymphoid tissue

(MALT), 97

Multi-infarct dementia, 427 Multifocal atrial tachycardia, 179 Multinodular goiter, toxic, 25 Multinucleated giant cells, 443 Multiple endocrine neoplasia

(MEN I and II)

RET mutations in, 32

thyroid medullary carcinoma and, 32 Zollinger-Ellison syndrome and, 97


Multiple myeloma, 213–214

Multiple sclerosis, 424–426 Mupirocin

for folliculitis, 442

for impetigo, 441 Murmurs

in aortic regurgitation, 167 chest pain syndromes and, 126

systolic, effect of maneuvers on, 166 Muscarinic effects, in organophosphate

poisoning, 389

Musculoskeletal disorders, chest pain and, 130

Myasthenia gravis, 421–422

Mycetoma, 280

Mycobacterium avium complex, in AIDS, 274

Mycobacterium tuberculosis, 243

Mycophenolate therapy, 423

for nephrotic syndrome, 297 for SLE, 69

Mycoplasma, as pneumonia cause, 239, 240

Mydriasis, 328

Myelodysplastic syndrome (MDS), 212 Myeloma, multiple, 213–214 Myocardial disease, 168–171. See also

Cardiomyopathy

Myocardial infarction (MI)

with ST elevation. See ST elevation myocardial infarction (STEMI)

without coronary atherosclerosis, 149 without ST elevation, unstable angina

and, 137, 138–140

Myocardial ischemia, in IHD, 133 Myocardial perfusion imaging, 146 Myocarditis, 271

chest pain and, 129, 130 Myoglobins

in acute renal failure, 287–288 in chest pain evaluation, 128

Myopathies, inflammatory, 83–84 Myotomy, for achalasia, 87 Myxedema, pretibial, 25

Myxedema coma, 30


N

N-acetyl cysteine (NAC), for

acetaminophen toxicity, 379

Nafcillin, 225, 226



USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.


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Naloxone, in toxic ingestion/overdose management, 377

Narrow complex tachycardia, 370

Nasal polyposis, aspirin-sensitive asthma and, 335

Natalizumab, 425

Near-drowning, 401

Neck infections, 233–236 Necrosis, in acute pancreatitis, 117 Necrotizing fasciitis, 442–443

Nedocromil, 337 Needlestick injury

hepatitis viruses and, 123, 248, 251

HIV and, 278

Neighborhood signs, vertigo and, 416

Neisseria gonorrhoeae

septic arthritis and, 261–262 urethritis and, 251–252

Neisseria meningitidis, 229

Nephritis, allergic interstitial, 286–287 Nephrogenic diabetes insipidus (NDI),

19–21, 303

Nephrolithiasis, 310–311 Crohn disease and, 288

Nephrology. See Renal function and disease

Nephropathy analgesic, 290

diabetic, 45–46

hypertension and, 312, 315 immunoglobulin A (IgA), 294

Nephrotic syndrome, 296–297

Neuralgia, trigeminal, 420 Neuroleptic malignant syndrome, 399

Neurologic disease, hypertension and, 315 Neurology

cerebrovascular accident, 409–411

dementia, 426–428

Guillain-Barré syndrome, 420–421

headache disorders, 417–419

Huntington disease, 428–429

hypercalcemia and, 34

movement disorders, 428–431

myasthenia gravis, 421–422 seizures and epilepsy, 411–415 spinal cord diseases, 405–406 vertigo and dizziness, 415–417

Neuromuscular disorders

amyotrophic lateral sclerosis, 423–424 hyperparathyroidism and, 36

hypoparathyroidism and, 39


multiple sclerosis, 424–426

myasthenia gravis, 421–422 Neuropathy, in diabetes mellitus, 46–47 Neurosyphilis, 230, 253

Nevus, dysplastic, 448

New York Heart Association Functional Classification (NYHA staging system), 153–154

sexual activity risk and, 148 Newborn, hypothyroidism in, 29 Nicotinic effects, in organophosphate

poisoning, 389 Nikolsky sign

in pemphigus vulgaris, 434

in Staphylococcal scalded skin syndrome, 447

in toxic epidermal necrolysis, 437 Nil lesion nephrotic syndrome, 297 Nimodipine, 396, 411

Nissen fundoplication, in gastroesophageal reflux disease, 93

Nitrates

in acute coronary syndrome, 146 in cardiovascular disease, 188

Nitrites, in renal disease diagnosis, 298 Nitroglycerin (NTG)

for angina, 136

for congestive heart failure, 155 response to, chest pain and, 126 for unstable angina/NSTEMI, 140

Nitroprusside, for congestive heart failure, 155

Nocturnal cough, 335

Nocturnal desaturation, in COPD, 340 Nocturnal diarrhea, 105

Non-exertional heat disorders, 398

Non-Hodgkin lymphoma (NHL), 216–217 Non-insulin-dependent diabetes mellitus

(NIDDM), 40

Non-nucleoside reverse transcriptase inhibitors (NNRTIs), 277, 278

Non-ST elevation myocardial infarction (NSTEMI), unstable angina and, 137, 138–140

high-risk features in, 139 Nonatherosclerotic acute coronary

syndrome, 148–149 Noncardiogenic pulmonary edema, in

salicylate toxicity, 386 Nonendocrine tumors, in Cushing

syndrome, 49–51


Noninvasive ventilation (NIV), 333 Nonionizing radiation, injury from, 400 Nonproliferative retinopathy, 46, 465 Nonsteroidal antiinflammatory drugs

(NSAIDs)

acute renal failure and, 290 asthma and, 335

gout and, 79, 80

lithium poisoning and, 385 for migraine headaches, 418 for osteoarthritis, 78

peptic ulcer disease and, 76, 94 rheumatoid arthritis and, 66 for SLE, 69

Nonulcer dyspepsia, 99

Normal pressure hydrocephalus (NPH), 427 Normocytic anemia, 193

Nuclear medicine scan

in acute cholecystitis, 461 in osteomyelitis, 463

Nuclear stress test, in ischemic heart disease, 135

Nucleoside reverse transcriptase inhibitors (NRTIs), 277, 278

Nutcracker esophagus, 88 Nystagmus, vertigo and, 416


O

Obesity, as IHD risk factor, 132 Obstructive disease, pulmonary, 334–344.

See also Chronic obstructive pulmonary disease (COPD)

Obstructive shock, 191

Obstructive sleep apnea (OSA), 358 Occlusion, of central retinal vessels, 468 Octreotide, acromegaly and, 16 Odynophagia, 85, 89

Oligoarticular symmetric arthritis, 62 Onychomycosis, 439

Open-angle glaucoma, 469 Ophthalmology

cataracts, 470

conjunctival diseases, 470–471

glaucoma, 469–470

keratitis, 471

periorbital cellulitis, 471

retinal diseases, 465–469

uveitis, 471–472

Ophthalmopathy, in Graves’ disease, 26 Opiate overdose, 382



USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.

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Index



Opioid analgesics, for migraine headaches, 419

Opportunistic infections, in AIDS, 273–275 Oral candidiasis (thrush), 440

Oral hypoglycemic drugs, 41–42 Organophosphate poisoning, 389

Oropharyngeal dysphagia, 85 Orthostasis, in gastrointestinal bleeding,

114, 115

Osborne wave, 399

Osler’s nodes, in infective endocarditis, 267 Osmolar gap, 380

Osmotic fragility test, 206 Osteoarthritis (OA), 62, 77–78

acromegaly and, 16 joint aspiration in, 62

in metacarpophalangeal joints, 122 Osteodystrophy, in end-stage renal disease,

299

Osteomas, 113

Osteomyelitis, 260–261 imaging studies in, 463

Osteophytes, 77, 122 Osteoporosis, prevention of, 8 Otitis media, 233

Outpatient setting, for asthma patients, 336 Oxacillin, 225, 226

Oxalate crystals, acute renal failure and, 288 Oxygen delivery (Do2), gas exchange

disturbances and, 326

Oxygen supply/demand, shock syndromes and, 190–191

Oxygen therapy in asthma, 336

in carbon monoxide poisoning, 381 in COPD, 341, 342

supplemental. See Supplemental oxygen therapy

Oxytocin, pituitary gland and, 11


P

P-R waves, in AV block, 374 Pacemaker placement

in atrial dysrhythmias, 374 digoxin poisoning and, 387

Pacing, transcutaneous vs. transvenous, 374 Pain

abdominal, lead poisoning and, 384 chest. See Chest pain


epigastric, 92–99. See also Epigastric pain

on swallowing, 89 Pancreatic B-cell tumor, 47 Pancreatic pseudocyst, 118 Pancreatitis

acute, 116–118

autoimmune, 118

chronic, 108 epigastric pain in, 92 gallstone, 116, 117

severe necrotizing, 117

Pap smear, in cervical cancer screening, 2 Papillary carcinoma, of thyroid, 32 Papillary necrosis, acute renal failure and,

290

Papulosquamous dermatitis, 451–453

Parapneumonic effusion, 330 Parasitic infections, of skin, 445–446 Parathyroid glands, diseases of, 33–39 Parkinson disease, 429–431

dementia secondary to, 427 “Parkinson plus” syndromes, 429 Parkland formula, 397

Paronychia, 443

Candidal, 440

Paroxysmal nocturnal hemoglobinuria (PNH), 207

Paroxysmal supraventricular tachycardia, 178–179

Partial prothrombin time (PPT) in antiphospholipid antibody

syndrome, 65

in coagulopathies, 220–223 prolonged, causes of, 220

Partial seizures, 412

Partial thromboplastin time (PTT), in coagulopathies, 220–224

Patent foramen ovale, thromboembolism in, 351

Pediculosis, 445–446 Pegvisomant, acromegaly and, 17

Pelvic inflammatory disease (PID), 252 Pemphigus vulgaris, 434

Penicillins

allergic cross-reactivity and, 226 for bacterial infections of skin, 441 gram-negative bacilli and, 227 gram-positive cocci and, 225–226 skin reactions to, 435, 436

Pentamidine, acute renal failure and, 290


Peptic ulcer disease, 94–96 as chest pain cause, 129

Percutaneous coronary intervention (PCI), 137, 144, 145

indication for, 140

Pericardial disease, 272–275

Pericardial effusion, 173–174 Pericarditis

acute, 272–273

acute coronary syndrome and, 147 chest pain and, 129

constrictive, 174–175

Perilymphatic fistula, 416

Perinephric abscess, 259–260

Periorbital cellulitis, 471

Peripheral neuropathy, 46

Peritoneal mesothelioma, 349 Peritonitis

as dialysis complication in end-stage renal disease, 299

spontaneous bacterial, 119–120 Petechiae, in infective endocarditis, 267 Petit mal (absence) seizures, 412

Peutz-Jeghers syndrome, 113

PHAILS (mnemonic), charcoal therapy and, 377

Pharmacologic cardioversion, in atrial fibrillation, 182

Pharyngitis, 235

Phencyclidine (PCP), clearance time, 378 Phenylephrine handgrip, effect on systolic

murmurs, 166 Phenytoin therapy

adverse effects, 189

for seizures and epilepsy, 414–415 Pheochromocytoma, 56–57

secondary hypertension in, 316 Philadelphia chromosome, 210 Phlebotomy, for hemochromatosis, 122 Phosphatidyl inositol glycan A (PIG-A),

207

Photosensitivity rash/reaction

in porphyria cutanea tarda, 435 in SLE, 62, 69

Physical activity. See Exercise Physical examination, in chest pain

evaluation, 126–127 Physical therapy, in osteoarthritis, 77 Pick disease, 427

Pigments, acute renal failure and, 287–288 Pill esophagitis, 89


USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.


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Pitting edema, 153

Pituitary apoplexy, 17

Pituitary gland, 11–12

action, 13

adenomas, 13–17

anatomy, 12

diseases, 11–23

Pityriasis rosea, 452

Pityrosporum orbiculare, 439

Pityrosporum ovale, 452 Plasma cell disorders, 213–214

Plasma-to-urine osmolality, in diabetes insipidus, 20–21

Plasmapheresis

in Guillain-Barré syndrome, 421 as myasthenia gravis therapy, 422

Platelet disorders, 218–219

Pleural effusion, 328–332

in acute pancreatitis, 117 chest radiography in, 330

decubitus chest x-ray detecting, 456 Pleural mesothelioma, 349

Pleuritis, chest pain and, 130 Plummer disease, 25

Plummer-Vinson syndrome (PVS), 89 Pneumatic dilation, for achalasia, 87 Pneumococcal vaccination, 5, 242

Pneumoconiosis, 348–349

Pneumocystis jirovecii infection in AIDS, 273

as pneumonia cause, 239 Pneumocystis pneumonia (PCP), 240 Pneumonia, 238–242

chest x-rays in, 457–458 Pneumoperitoneum, 459 Pneumothorax, chest pain and, 130 Pneumovax, 4

Poison ivy, contact dermatitis and, 452 Polio vaccine, 4

Polyarteritis nodosa (PAN), 82, 293 Polyarticular symmetric involvement, in

rheumatoid diseases, 61 Polycystic kidney disease, 311 Polycythemia vera, 212–213

Polymyositis, 83–84 Porphyria cutanea tarda, 435

Portal hypertension, in liver disease, 119 Positive end-expiratory pressure (PEEP),

333–334

Positron emission tomography (PET), 462


Postantibiotic effect, in acute renal failure, 289

Postencephalic Parkinsonism, 429 Posterior-anterior (PA) chest x-rays, 455 Posterior cerebral artery (PCA) occlusion,

410

Posterior circulation syndromes, in cerebrovascular accident, 410

Posterior pituitary lobe, diseases of, 19–23 Postexposure prophylaxis, HIV and, 278 Postinfectious glomerulonephritis, 294

Postprandial hypoglycemia, 47

Postpubertal hypogonadism, 58

Postrenal azotemia, 282, 284

Postthrombotic syndrome, 356

Potassium hydroxide (KOH) test, 439, 440 Potassium-sparing diuretics

as antihypertensive, 316

in congestive heart failure, 156 Pre-excitation syndrome. See Wolff-

Parkinson-White (WPW) syndrome

Precancerous lesions, 447–448

Prednisone, in immune thrombocytopenic purpura, 218

Pregnancy

bacteriuria in, 298

contraindicated antihypertensives in, 317

in HIV-positive patients, 278 in hypertensive patients, 314

propylthiouracil for hyperthyroidism in, 27

in SLE, 70

thromboembolism in, 350

vaccinations and, 5, 6, 7

Preload increase/reduction, in HOCM, 170

Prerenal azotemia, 282–284 Pressure (decubitus) ulcers, 453 Presyncope, vertigo vs., 415 Pretibial myxedema, 25

Preventive medicine, 1–10 abdominal aortic aneurysm, 8 alcohol abuse, 9

cancer screening, 1–3 hypertension, diabetes, and

hypercholesterolemia, 9

immunizations, 4–7

osteoporosis, 8

smoking cessation, 9


travel medicine, 3–4

violence and injury, screening for, 10 Primary biliary cirrhosis, 121

Primary hyperaldosteronism, 52 secondary hypertension in, 316

Primary hyperparathyroidism, 33, 36–37, 38

Primary hyperthyroidism, 26

Primary hypothyroidism, 30

Primary progressive multiple sclerosis, 424 Primary sclerosis cholangitis, 122 Prinzmetal angina, 149

Probenecid, gout and, 79, 80 Procainamide, adverse effects, 189 Prolactin, hyperprolactinemia and, 14 Prolactinomas, 14

Prolapse, mitral valve, 163–164 Proliferative retinopathy, 46, 465 Propafenone, adverse effects, 189 Prophylaxis

opportunistic infections in AIDS, 273–275

postexposure, HIV and, 278 traveler’s diarrhea and, 104

Propionibacterium acnes, 454 Propranolol

for hyperthyroidism, 27

for migraine headaches, 419 Propylthiouracil (PTU), for

hyperthyroidism in pregnancy, 27 Prostate screening, 2

Protease inhibitors

acute renal failure and, 290

as antiretroviral therapy, 277, 278

boosted, 278

Proteinuria, in renal disease diagnosis, 298 Prothrombin time (PT)

in coagulopathies, 220–223 in Crohn disease, 100 prolonged, causes of, 220

Proton-pump inhibitors (PPIs) for Barrett esophagus, 94

for gastroesophageal reflux disease, 93, 94

for peptic ulcer disease, 95–96

for Zollinger-Ellison syndrome, 98 Proximal renal tubular acidosis, 309 Prussian Blue stain, in sideroblastic

anemia diagnosis, 197

Pseudocyst, pancreatic, 118

Pseudogout, 80

joint aspiration in, 62–63



USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.

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Pseudohyperkalemia, 304

Pseudotumor cerebri, 419–420

Psoriasis, 451

Psoriatic arthritis, 74, 76

Psuedocalcemia, 38

Psychosis, Korsakoff, 390, 391 Pulmonary disease

adult respiratory distress syndrome, 357 asthma, 334–338

atelectasis, 360

chest pain in, differential diagnosis, 129 chest radiography in, 327–332

COPD, 339–343

diagnostic tests in, 321–326

gas exchange disturbances in, 326–327 interstitial lung diseases, 345–349 lung cancer, 358–360

obstructive, 334–344

pleural effusions, 328–332

pulmonary nodule, 328

pulmonary thromboembolism, 350–357

sleep apnea, 357–358

ventilation and, 333–334 Pulmonary edema

causes, 158–159

in congestive heart failure, 151, 153, 159 noncardiogenic, in salicylate

intoxication, 386 Pulmonary embolism (PE), 350. See also

Deep vein thrombosis (DVT) chest pain and, 129

general diagnostic concepts for, 354 management algorithm, 355

Wells’ criteria for, 352

Pulmonary function tests (PFTs), 321–326 in COPD, 340

Pulmonary indices, 323

Pulmonary nodule, 328

Pulmonary thromboembolism, 350–357. See also Deep vein thrombosis (DVT); Pulmonary embolism (PE)

acute coronary syndrome and, 147 Pulmonic stenosis, in aortic stenosis

differential diagnosis, 165 Pulmonology. See Pulmonary disease Pulse oximetry, in carbon monoxide

poisoning, 381

Pulseless arrest management algorithm, 187, 363

Pulseless electrical activity (PEA), 368–369


Pump dysfunction, in acute coronary syndrome, 147

Purified protein derivative (PPD), in tuberculosis testing, 244, 245

Pyelonephritis, acute bacterial, 259 Pyoderma gangrenosum, 76

Pyrazinamide (PZA), 244


Q

Q-fever, 239, 242 QRS complex

in atrial dysrhythmias, 369

in normal complex tachycardia, 370 systolic dysfunction and, 158

in torsade de Pointes, 186

in tricyclic antidepressant toxicity, 388 in ventricular fibrillation, 365

in ventricular tachycardia, 184, 185 QT interval

in torsade de Pointes, 186

in ventricular tachycardia, 367 Quinidine, adverse effects, 189 Quinolones, 227–228

Quinupristin/dalfopristin, 227


R

Rabies, 403–404

vaccine for, 4, 403–404

Radiation injuries, 400–401 Radioactive iodine. See Iodine therapy Radiology

abdominal x-rays, 460–462

bone imaging, 463

central nervous system visualization and, 463

chest x-rays. See Chest x-rays PET scanning, 462

Rapidly progressive glomerulonephritis (RPGN), idiopathic, 295

Rate and rhythm disturbances, cardiac, 176–187

Rate control

in atrial fibrillation, 182, 183, 371, 372

ventricular, 183

Raynaud disease, 71

Raynaud phenomenon, 71 in systemic sclerosis, 62

Reactive arthritis, 74, 75 Reed-Sternberg cell

Hodgkin disease and, 214, 215 non-Hodgkin lymphoma and, 216


Regurgitation aortic, 166–167

mitral. See Mitral regurgitation Reidel thyroiditis, 31

Reiter syndrome

keratoderma blennorrhagia in, 76 reactive arthritis and, 75

Relapsing remitting multiple sclerosis, 424, 425

Renal artery stenosis, 283

secondary hypertension in, 315–316 Renal biopsy, in glomerulonephritis, 291 Renal failure, contrast-induced, 291 Renal function and disease

acid/base disturbances, 305–308 acute renal failure, 281–290

in diabetes mellitus, 45–46 diagnostic testing for, 297–298 end-stage renal disease/dialysis,

298–300

fluid/electrolyte disorders, 300–305

glomerulonephritis, 291–297 hereditary cystic disease, 311 hypercalcemia and, 34

hypertension and, 312–318 lithium poisoning and, 385 nephrolithiasis, 310–311

renal insufficiency, 281

renal transplantation, 300 renal tubular acidosis, 308–310

Renal insufficiency. See Azotemia

Renal proteinuria, hypertension and, 313 Renal transplantation, 300

Renal tubular acidosis, 308–310 distal (type I), 308–309

hyporeninemic/hypoaldosteronism (type IV), 309–310

proximal (type II), 309

Reperfusion therapy, in STEMI, 143–144 adjuvant therapy with, 144–145

Reproductive organs, radiation injury to, 400

Residual volume (RV), 321, 323

Respiratory acidosis, 308

Respiratory alkalosis, 306

Respiratory function, in salicylate toxicity, 386

Respiratory injury, from smoke inhalation, 396, 397

Restless leg syndrome (RLS), 431



USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.


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Restrictive cardiomyopathy, 171 morphologic and hemodynamic

characteristics, 168 Resuscitation

cardiac dysrhythmias and, 364–375 cardiopulmonary. See

Cardiopulmonary resuscitation (CPR)

of drowning victims, 401–402 fluids, in burn injury, 397

RET mutations, in thyroid neoplasia, 32 Retapamulin, 441

Retinal artery occlusion, central, 468 Retinal detachment, 466–467

Retinal hemorrhage, 468

Retinal vein occlusion, central, 468 Retinopathy

diabetic, 46, 465–466

hypertension and, 313, 315 Retrograde memory loss, head trauma

and, 391

Revascularization, in unstable angina/ NSTEMI, 140

Rewarming therapy, in hypothermia, 399 Rhabdomyolysis

in acute renal failure, 287–288 in malignant hyperthermia, 399

in neuroleptic malignant syndrome, 399 Rheumatoid arthritis (RA), 65–68 Rheumatoid factors (RFs), 64 Rheumatology

arthritis evaluation, 61–62

crystal-induced arthropathies, 78–80

drug-induced lupus, 70

erythema nodosum, 76

inflammatory myopathies, 83–84

osteoarthritis, 77–78

psoriatic arthritis, 76

rheumatoid arthritis, 65–68

scleroderma, 70–72

septic arthritis, 81

seronegative arthropathies, 73–76

Sjögren syndrome, 72–73

spondyloarthropathies, 73–76 systemic lupus erythematosus, 68–70 testing in, 62–65

vasculitis syndromes, 81–83

RhoGam™, 218

Rhythm disturbances. See also

Arrhythmias; Dysrhythmias control in atrial fibrillation, 182, 372


sinus node dysfunction, 176–185 torsade de Pointes, 186–187 ventricular fibrillation, 365

Ribavirin therapy, in rabies, 403

Rickettsia rickettsii, 272

Rifampin (Rif), for tuberculosis, 244 Rifaximin, 104

Right ventricular infarction, 147 Riluzole therapy, in ALS, 423 Ringer’s lactate, in burn injury

management, 397

Ritonavir, 278

Rituximab, 206, 218

Rivaroxaban, 372

Rocky Mountain spotted fever (RMSF), 272 meningitis and, 229

Roth’s spots, in infective endocarditis, 267 “Rule of nines,” in skin injury assessment,

397


S

Sacroiliitis, 75

Salicylate intoxication, 386–387

Salmonella infection

infectious diarrhea and, 102, 103, 104 reactive arthritis and, 75

Samter’s triad (aspirin-sensitive asthma), 335

Sarcoidosis, 346–348

SARS, as pneumonia predisposition, 239 Scabies, 445

Scalded skin syndrome, staphylococcal, 446–447

Scaling disorders, of skin, 451–453 Schatzki’s ring, esophageal, 89 Schilling test, 201

Schirmer’s test, 73

Schober test, 74

Sclerodactyly, in CREST syndrome, 71 Scleroderma, 70–72

esophageal involvement in, 88 shiny skin in, 71

Scleroderma renal crisis, 71 Scromboid poisoning, 103, 104

Seawater drowning, 401

Seborrheic dermatitis, 452

Seborrheic keratosis, 447–448

Second-degree AV block, 177, 373, 374

Second-degree burns, 397

Secondary hyperaldosteronism, 52

Secondary hyperparathyroidism, 38


Secondary hypertension, 313, 315–316 Secondary progressive multiple sclerosis,

424, 425

Seizure disorders, 411–415

toxin-elated seizure, 378 Selegiline, in Parkinson disease, 431 Semisynthetic penicillinase-resistant

penicillins, 225–226

Septic arthritis, 81, 261–262 joint aspiration in, 62–63

Seronegative arthropathies, 73–76 Serum ascites albumin gradient (SAAG),

120

Serum osmolality, in hyponatremia, 300 Severe necrotizing pancreatitis, 117

Sex, as IHD risk factor, 133 Sex hormones, IHD and, 133

Sexual activity, acute coronary syndrome and, 148

Sexually transmitted diseases (STDs), 251–257

Sheehan postpartum necrosis, 17

Shigella infection

infectious diarrhea and, 103, 104 reactive arthritis and, 75

Shingles vaccine, 7

Shock syndromes, 190–191 Sickle cell disease, 203–204 Sickle cells, 204

Sickle trait, 203

Sickledex screening test, 204 Sideroblastic anemia, 197–198

iron indices in, 199

Sigmoidoscopy, in colon cancer diagnosis, 112

Silicosis, 349

Simple cysts, 311

Simple seizures, 412

Sinus bradycardia, 176, 373, 374

Sinus node function, disorders of, 176 –185 Sinus tachycardia, 178

Sinusitis, 234–235

Sjögren syndrome, 62, 72–73 Skin

anatomy, 433

burn injuries to, 396–398 in scleroderma, 70, 71

toxidromes, physical findings in, 376 warfarin-induced necrosis, 356

Skin cancers, 448–450



USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.

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Skin infections bacterial, 441–443

fungal, 439–440

genital warts, 257

methicillin-resistant Staphylococcus aureus, 228

MRSA, antibiotics for, 228 viral, 443–445

Skull fracture, depressed, 393 Sleep apnea, 357–358

Slit-lamp examination, in Wilson disease, 122, 123

Small cell carcinoma, of lung, 359 Smoke inhalation injuries, 396 Smoking

COPD risk and, 340 as IHD risk factor, 132 lung cancer and, 358

Smoking cessation

as COPD management strategy, 341 as preventive medicine, 7–8

“Smudge cells,” 211

Snakebites, 404

Sofosbuvir/ledipasvir (Harvoni), 124, 250,

251

Somogyi effect, 47

Sonography, in abdominal imaging, 460 Sore throat, S. pyogenes and, 235 Spherocytosis, hereditary, 206

Spinal artery occlusion, anterior, 407 Spinal cord diseases

anterior spinal artery occlusion, 407 Brown-Séquard syndrome, 408

cord compression, 405–406

subacute combined degeneration, 407 syringomyelia, 406–407

Spine fractures, in ankylosing spondylitis, 74

Spironolactone, in congestive heart failure, 156

Splenectomy

in immune thrombocytopenic purpura, 218

vaccinations prior to, 4 Splenic vein thrombosis, in acute

pancreatitis, 117 Splinter hemorrhage, in infective

endocarditis, 267

Spondyloarthropathies, 73–76 Spontaneous bacterial peritonitis (SBP),

119–120


Squamous cell carcinoma of lung, 359

of skin, 449

Squatting, effect on systolic murmurs, 166 ST elevation myocardial infarction

(STEMI), 140–146

EKG tracings, 142

evolution, 143

localization, 143 ST segment

in acute pericarditis, 172–173 in ischemic heart disease, 135

STEMI. See ST elevation myocardial infarction (STEMI)

Stable angina

chest pain quality in, 125

ischemic heart disease and, 133–137 Staphylococcal scalded skin syndrome

(SSSS), 446–447

differential diagnosis, 446

Staphylococcus/Staphylococcus aureus

infection antibiotics for, 441 brain abscess and, 232

infectious diarrhea and, 103 meningitis and, 229

methicillin-resistant. See Methicillin- resistant Staphylococcus aureus (MRSA)

as pneumonia predisposition, 239 in scalded skin syndrome, 446–447 septic arthritis and, 81

toxic shock syndrome and, 446 Stasis dermatitis, 452

Statins, in acute coronary syndrome, 146 Status epilepticus, 412

development of, 414

Steatorrhea, 108 Stenosis

aortic. See Aortic stenosis mitral, 160–161 pulmonic vs. aortic, 165

renal artery. See Renal artery stenosis Steroids

for inflammatory bowel disease, 100 for nephrotic syndrome, 297

peptic ulcer disease and, 94 for sarcoidosis, 348

Stevens-Johnson syndrome, 437 Stool studies, in inflammatory bowel

disease, 100


Strep throat, 235 Streptococcal bacteria

brain abscess and, 232 Gram-positive, 225 necrotizing fasciitis and, 442 pharyngitis and, 235

as pneumonia cause, 238–239

in postinfectious glomerulonephritis, 294

skin infections and, 441

Streptococcus bovis, 111, 113

Streptococcus pneumoniae, 229, 238–240 Stress, IHD and, 133

Stress testing, in IHD, 135–136 Stroke, 409–411

hypopituitarism and, 18 Subacute combined spinal cord

degeneration, 407

Subacute (de Quervain) thyroiditis, 25, 30–31

Subacute infective endocarditis, 266 Subarachnoid hemorrhage (SAH),

394–396

in cerebrovascular accident, 411 CT sensitivity in, 463 traumatic, 391

Subconjunctival hemorrhage, 471

Subdural hematoma, 391, 392, 393, 394 Sudden cardiac death, 147 Sulfasalazine, in RA management, 67

Sulfonylureas, for diabetes mellitus, 41, 42 Sun protection, for SLE patients, 69 Supplemental oxygen therapy

in asthma, 336

in COPD, 341, 342

Supply ischemia, 133

Supratherapeutic INR, 224

Supraventricular arrhythmias, 178–183 Supraventricular tachycardia (SVT), 185,

369–373

Surgery. See also Transplantation; specific procedures

mitral valve replacement, 161, 163 in necrotizing fasciitis, 442

in osteoarthritis, 78

in Parkinson disease, 431

in peptic ulcer disease, indications for, 96

in STEMI, 145

Swallowing

difficulty in, 85

pain on, 85, 89



USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.


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Swan-Ganz catheterization, in ARDS, 357 Symptom-triggered therapy, in alcohol

withdrawal management, 390

Syncope

head trauma and, 392 seizure vs., 412

Syndrome of inappropriate secretion of ADH (SIADH), 22, 302–303

Synovial fluid analysis, 62–63 Syphilis, 252–254

Syringomyelia, 406–407

Systemic lupus erythematosus (SLE), 62, 68–70

antinuclear antibodies in, 64 glomerulonephritis and, 295

malar rash in, 62, 69

Systemic sclerosis (SSc), 62, 70–72 progressive, esophageal involvement

in, 88

Systolic dysfunction, in congestive heart failure, 151

agents lowering mortality in, 156 medical devices for, 158

Systolic murmur, effect of maneuvers on, 166


T

T lymphocytes, rheumatoid arthritis and, 65 Tabes dorsalis, in syphilis, 253

Tachycardia

atrial, 366, 370

narrow/wide complex, 370

with pulses, management algorithm for, 366

supraventricular, 185, 369–373 ventricular. See Ventricular tachycardia

(VT)

Telangiectasias, in CREST syndrome, 71 Telavancin, 227

Telbivudine, for hepatitis infection, 250 Telogen effluvium, 453

Temporal arteritis (TA), 83, 417 Tenofovir, for hepatitis infection, 250 Tension-type headache, 418

Terbinafine, 439

Terfenadine, 436

Tertiary hyperparathyroidism, 38

Testicular diseases, 57–58

Testosterone therapy, 58

Tetanus, 279

vaccine for, 5


Tetrabenazine, in Huntington disease, 428 Tetrahydrocannabinol (THC), clearance

time, 378

Thalassemia, iron indices in, 198–199 Thalassemia trait, 199

Theophylline

for asthma, 336, 337

for COPD, 341

Theophylline toxicity, in COPD, 342 Thiamine

for alcohol withdrawal-related syndromes, 391

in toxic ingestion/overdose

management, 377 Thiazide diuretics

as antihypertensive, 316

for congestive heart failure, 155, 156

Thiazolidinediones, 41, 42

Third-degree burns, 397

Third-degree (complete) AV block, 178 Thoracocentesis, 330

Thrombocythemia, essential, 213

Thrombocytopenia, heparin-induced, 223 in pulmonary thromboembolism, 355

Thrombocytopenic purpura immune, 218

thrombotic, 222–223

Thromboembolic disease, 350–357. See also Deep vein thrombosis (DVT); Pulmonary embolism (PE)

acute coronary syndrome and, 147 Thrombolytics

antithrombin therapy with, 145 NSTEMI and, 141

for pulmonary thromboembolism, 355 for STEMI, 143–144

Thrombosis

heparin-induced thrombocytopenia and, 223

in paroxysmal nocturnal

hemoglobinuria, 207 Thrombotic thrombocytopenic purpura

(TTP), 222–223

Thrush (oral candidiasis), 440 Thymectomy, 423

Thymoma, 423

Thyroid gland diseases, 23–33 neoplasia, 31–33

Thyroid hormones, 23

synthesis and secretion pathways, 24 thyroid function and, 25


Thyroid-reactive iodine uptake (RAIU), 24, 25

Thyroid-stimulating hormone (TSH), 23, 25

in hypothyroidism diagnosis, 30 Thyroid stimulating immunoglobulin (TSI), 25, 26, 27, 28

Thyroid storm, 28

Thyroiditis, 30–31

Thyrotoxicosis, 25–28

amiodarone-induced, 29 atrial fibrillation in, 373

Thyrotropin-releasing hormone (TRH), hyperprolactinemia and, 14

Thyrotropin (TSH) hyperprolactinemia and, 14

hypopituitarism and, 18

l-Thyroxine (T4), 18, 23, 28, 30, 31, 32

Tic douloureux, 420

Tigecycline, 227

Tinea capitis, 439

Tinea corporis, 439

Tinea cruris, 439

Tinea pedis, 439

Tinea versicolor, 439–440 Tinnitus

in salicylate toxicity, 386 vertigo and, 416

Tissue plasminogen activator (tPA), for cerebrovascular accident, 410–411

Tizanidine therapy, in ALS, 423 TMP/SMX therapy

for diarrhea, 104 for skin MRSA, 228

Tocainide, adverse effects, 189

Tonic-clonic (grand mal) seizures, 412 Topiramate, 419

Torsade de Pointes, 186–187

ventricular tachycardia and, 367–368 Total lung capacity (TLC), 321, 323 Toxic diffuse goiter (Graves’ disease), 25,

26–28

Toxic epidermal necrolysis (TEN), 437–438

Toxic multinodular goiter (Plummer disease), 25

Toxic shock syndrome (TSS), 446 Toxicology

acetaminophen poisoning, 378–379

acids/alkalis, 381–382



USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.

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Index



alcohol withdrawal-related syndromes, 390–391

anticholinergic poisoning, 388–389 carbon monoxide poisoning, 380–381 caustics/corrosives, 380–381

digitalis, 156–157

digoxin, 157

digoxin poisoning, 387

drug abuse, 382–384 drug clearance times, 378

ethylene glycol ingestion, 379–380 heavy metals exposure, 384

initial evaluation, 376

isopropyl alcohol ingestion, 380 methanol ingestion, 379–380

organophosphate poisoning, 389

salicylates, 386–387

toxic ingestion/overdose management, 377–378

toxidrome physical findings, 376 tricyclic antidepressants, 388

Toxicology screen, 378

Toxidromes, 376 Toxin exposures

acute renal failure and, 289–290 Staphylococcal scalded skin syndrome,

446–447

toxic shock syndrome, 446 Toxoplasmosis

brain abscess and, 233

in HIV/AIDS, 232, 274–275

Transcutaneous vs. transvenous pacing, 374 Transferrin saturation test, 122 Transfusion therapy

in anemia, 194

in radiation injury management, 401 in sickle cell disease, 204

Transient hyperthyroidism, 25 Transjugular intrahepatic portosystemic

shunting (TIPS), 114 Transplantation

bone marrow, in radiation injury management, 401

renal, 300

Transudative pleural effusion, 328 Trauma, to head, 391–394 Traumatic arthritis, 62

Travel medicine, 3–4 Traveler’s diarrhea

management, 104

prevention, 4


Tremor. See Essential tremor Treponema pallidum, 252 Tricyclic antidepressants

for migraine headaches, 419 toxicity and overdose of, 388

Trigeminal neuralgia, 420

l-3,5,5’-Triiodothyronine (T3), 18, 23 Tropheryma whippelii biopsy, 109 Tropical sprue, 109

Troponins, cardiac, in chest pain evaluation, 127–128

Trousseau sign, 39

Tuberculosis, 243–245 Tubulointerstitial disease, acute renal

failure and, 285–290 Tumor lysis syndrome (TLS), 217

Tumor necrosis factor (TNF) inhibitors, in RA management, 67

Turcot syndrome, 113

Turner’s sign, 117

Two-dimensional echocardiography, in mitral valve prolapse, 164

Typhoid vaccine, 4

Tzanck smear, 443, 444


U

Ulcerative colitis (UC), 100–101 enteropathic arthropathy in, 76 primary sclerosis cholangitis and, 122

Ulcers

decubitus (pressure), 453 foot, in diabetes mellitus, 46

Ultrasound, in abdominal imaging, 460 Ultraviolet (UV)-B light sensitivity, in

SLE, 68

Unstable angina (UA), 137, 138–140 high-risk features in, 139

Urate, in acute renal failure, 288

Urate crystals, in acute renal failure, 288 Uremia, acute renal failure and, 281–282 Urethritis, 251–252

Uric acid stones, in nephrolithiasis, 310 Uric acid toxicity, in acute renal failure, 288 Urinalysis

in porphyria cutanea tarda, 435

in renal disease diagnosis, 297–298 Urinary tract infection (UTI), 258–260 Urine immunoassay, in toxicology screen,

378

Urine output

in lead poisoning, 384


in salicylate poisoning, 386 in toxic ingestion/overdose

management, 377

Uroporphyrins, urinary, 435

Urticaria, drug reactions causing, 435–436 Uveitis, 471–472


V

Vaccines

diphtheria/tetanus, 5

hepatitis A virus, 3, 6, 251

hepatitis B virus, 3, 5, 251

herpes zoster, 7

in HIV-positive persons, 275 human papillomavirus, 7

influenza, 5, 236

measles, mumps, rubella, 6 meningococcal, 5, 6

pneumococcal, 5, 242, 343

polio, 4

rabies, 4

shingles, 7

tuberculosis, 243

typhoid, 4

varicella, 6

Vagal maneuvers, for supraventricular tachycardia, 371

Valganciclovir, 274 Valproic acid

for migraine headaches, 419

for seizures and epilepsy, 414–415 Valsalva maneuver

effect on systolic murmurs, 166

in supraventricular tachycardia, 371 Valvular heart disease, 160–167

aortic regurgitation, 166–167

aortic stenosis, 164–166

mitral regurgitation, 161–163

mitral stenosis, 160–161 mitral valve prolapse, 163–164

Vancomycin

acute renal failure and, 290 for gram-positive cocci, 227 for meningitis, 230

Varenicline, contraindicated in psychiatric disease, 8

Varicella vaccine, 6

Varices, esophageal, 114

Vascular dementia, 427 Vascular diseases

hypopituitarism and, 13



USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.


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USMLE Step 2 CK l Internal Medicine



micro-/macro-, as diabetes

complication, 45

Vasculitis syndromes, 81–83 Vasodilators

as antihypertensive, 318

in congestive heart failure, 154–155 Vasopressin. See also Antidiuretic hormone

(ADH)

diabetes insipidus and, 20, 21, 120 excess of, syndromes associated with, 22 pituitary gland and, 11

syndrome of inappropriate secretion of ADH, 22

Venomous bites and stings, 402–404 Venous blood gases, in carbon monoxide

poisoning, 380, 381

Ventilation, 333–334

Ventilation-perfusion (V/Q) scan, 353 Ventricular arrhythmias, 184–185

Ventricular fibrillation, 365 Ventricular rate control, in atrial

fibrillation, 183 Ventricular septal defect, effect of

maneuvers in, 166

Ventricular tachycardia (VT), 184–185, 367–368

management algorithm, 183, 366

supraventricular, 185, 369–373

Verapamil, 419

adverse effects, 189

Vertigo, 415–417

Vestibular disease, vertigo and, 415

Vibrio parahaemolyticus, infectious diarrhea and, 103, 104

Vibrio vulnificus

hemochromatosis and, 122

infectious diarrhea and, 103, 104

Viekira Pak, 250

Violence, screening for, 10 Viral infections

hepatic, 248–251. See also Hepatitis

entries

infectious diarrhea and, 103, 104

of skin, 443–445

Viral load monitoring, in AIDS, 276 Viral sensitivity/resistance monitoring, in

AIDS, 276

Virtual colonoscopy, 462


Vital capacity (VC), 321, 323

Vitamin B12 (cyanocobalamine) deficiency, 200–201

in subacute combined spinal cord degeneration, 407

Vitamin B12 (cyanocobalamine) malabsorption, 108

Vitamin K deficiency, 221 VITAMINS mnemonic, 412

Vomiting, induced, in toxic ingestion/ overdose management, 377

von Willebrand disease (vWD), 218–219 Voriconazole, 280

Vulvovaginitis, 440


W

Wallenberg syndrome, 410 Warfarin

in acute coronary syndrome, 146 coagulopathy and, 223–224

for pulmonary thromboembolism, 355–356

Warts, genital, 257 Water restriction test, 21 Weber syndrome, 410

Wegener granulomatosis (WG), 62, 81–82,

292

Wells’ criteria, for pulmonary embolism risk, 352

Wenckebach AV block, 177, 373, 374

Wernicke encephalopathy, 390, 391

Westermark sign, 353 Wheals, in urticaria, 435 Whipple’s disease, 108, 109

“White coat hypertension,” 313

Whole bowel irrigation, in toxic ingestion/ overdose management, 377

Wide complex tachycardia, 370 Wilson disease, 122–123 Withdrawal/Withdrawal syndromes,

alcohol-related, 390–391

Wolff-Chaikoff effect, 28

Wolff-Parkinson-White (WPW) syndrome, 183–184, 185

atrial fibrillation in, 373 Wound management, 279


X

X-rays

abdominal, 460–462

in ankylosing spondylitis, 74–75 cervical spine, 74–75, 392

chest. See Chest x-rays in head trauma, 392

Xanthochromia, in subarachnoid hemorrhage, 396


Y

Yersinia

hemochromatosis and, 122

infectious diarrhea and, 103, 104

Yersinia pestis, as pneumonia

predisposition, 239


Z

Zenker diverticulum, 90–91

Zidovudine (AZT), 278

Zollinger-Ellison syndrome (ZES), 97–98 peptic ulcer disease and, 95

Zostavax, 5



USMLE® is a joint program of The Federation of State Medical Boards of the United States, Inc. and the National Board of Medical Examiners.

496